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Balancing self-renewal against genome preservation in stem cells: How do they manage to have the cake and eat it too?

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Abstract

Stem cells are endowed with the awesome power of self-renewal and multi-lineage differentiation that allows them to be major contributors to tissue homeostasis. Owing to their longevity and self-renewal capacity, they are also faced with a higher risk of genomic damage compared to differentiated cells. Damage on the genome, if not prevented or repaired properly, will threaten the survival of stem cells and culminate in organ failure, premature aging, or cancer formation. It is therefore of paramount importance that stem cells remain genomically stable throughout life. Given their unique biological and functional requirement, stem cells are thought to manage genotoxic stress somewhat differently from non-stem cells. The focus of this article is to review the current knowledge on how stem cells escape the barrage of oxidative and replicative DNA damage to stay in self-renewal. A clear statement on this subject should help us better understand tissue regeneration, aging, and cancer.

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Abbreviations

ABC:

ATP-binding cassette

ALT:

Alternative lengthening of telomere

Alt-NHEJ:

Alternative non-homologous end-joining

APB:

ALT-associated PML bodies

ATM:

Ataxia telangiectasia mutated

ATR:

Ataxia telangiectasia and Rad3 related

ATRX:

Alpha thalassemia/mental retardation syndrome X-linked (also known as RAD54)

BLM:

Bloom helicase

BRCA1/2:

Breast cancer 1/2

CO-FISH:

Chromosome orientation fluorescence in situ hybridization

C-NHEJ:

Classical non-homologous end-joining

CtBP:

C-terminal binding protein

CtIP:

CtBP interacting protein

DDR:

DNA damage response

DNA-PKcs:

DNA-dependent protein kinase catalytic subunit

DSBs:

Double-stranded breaks

ECTR:

Extrachromosomal telomere repeats

ERCC1:

Excision repair cross-complementation group 1

ERCC4:

Excision repair cross-complementation group 4 (also known as XPF)

ES:

Embryonic stem

FANCD1:

Fanconi anemia complementation group D1

HLTF:

Helicase-like transcription factor

HR:

Homologous recombination

ICL:

Interstrand crosslink

iPS:

Induced pluripotent stem

IR:

Ionizing radiation

KD:

Knock-down

KO:

Knock-out

MDR:

Multidrug resistance

MRN:

MRE11/RAD50/NBS1

MSH2:

mutS homolog 2

NS:

Nucleostemin

PARP1/2:

Poly(ADP)ribose polymerase 1 or 2

PCNA:

Proliferating cell nuclear antigen

PML:

Promyelocytic leukemia protein

RFC:

Replication factor C

RPA:

Replication protein A

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

SHPRH:

SNF2 histone-linker PHD ring helicase

SSA:

Single strand annealing

SSBs:

Single-stranded breaks

ssDNA:

Single-stranded DNA

TERC:

Telomerase RNA component

TERT:

Telomerase reverse transcriptase

TLS:

Translesion synthesis

TopBP1:

Topoisomerase II binding protein 1

TRF1:

Telomeric repeat factor 1

T-SCE:

Telomere sister chromatid exchange

XLF:

XRCC4-like factor (also known as Cernunnos)

XRCC1:

X-ray repair cross-complementing group 1

WRN:

Werner syndrome ATP-dependent helicase

References

  1. Fuchs E, Segre JA (2000) Stem cells: a new lease on life. Cell 100(1):143–155

    Article  CAS  PubMed  Google Scholar 

  2. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255(5052):1707–1710

    Article  CAS  PubMed  Google Scholar 

  3. Davis AA, Temple S (1994) A self-renewing multipotential stem cell in embryonic rat cerebral cortex. Nature 372(6503):263–266

    Article  CAS  PubMed  Google Scholar 

  4. Tsai RY (2004) A molecular view of stem cell and cancer cell self-renewal. Int J Biochem Cell Biol 36(4):684–694

    Article  CAS  PubMed  Google Scholar 

  5. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  6. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111

    Article  CAS  PubMed  Google Scholar 

  7. Wang JC, Dick JE (2005) Cancer stem cells: lessons from leukemia. Trends Cell Biol 15(9):494–501

    Article  CAS  PubMed  Google Scholar 

  8. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367(6464):645–648

    Article  CAS  PubMed  Google Scholar 

  9. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737

    Article  CAS  PubMed  Google Scholar 

  10. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63(18):5821–5828

    CAS  PubMed  Google Scholar 

  12. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65(23):10946–10951

    Article  CAS  PubMed  Google Scholar 

  13. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121(6):823–835

    Article  CAS  PubMed  Google Scholar 

  14. O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110

    Article  PubMed  CAS  Google Scholar 

  15. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1(3):313–323

    Article  CAS  PubMed  Google Scholar 

  16. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, Frank MH (2008) Identification of cells initiating human melanomas. Nature 451(7176):345–349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mandal PK, Blanpain C, Rossi DJ (2011) DNA damage response in adult stem cells: pathways and consequences. Nat Rev Mol Cell Biol 12(3):198–202

    Article  CAS  PubMed  Google Scholar 

  18. Naka K, Hirao A (2011) Maintenance of genomic integrity in hematopoietic stem cells. Int J Hematol 93(4):434–439

    Article  CAS  PubMed  Google Scholar 

  19. Nagaria P, Robert C, Rassool FV (2013) DNA double-strand break response in stem cells: mechanisms to maintain genomic integrity. Biochim Biophys Acta 1830(2):2345–2353

    Article  CAS  PubMed  Google Scholar 

  20. Rocha CR, Lerner LK, Okamoto OK, Marchetto MC, Menck CF (2013) The role of DNA repair in the pluripotency and differentiation of human stem cells. Mutat Res 752(1):25–35

    Article  CAS  PubMed  Google Scholar 

  21. Cervantes RB, Stringer JR, Shao C, Tischfield JA, Stambrook PJ (2002) Embryonic stem cells and somatic cells differ in mutation frequency and type. Proc Natl Acad Sci USA 99(6):3586–3590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tilgner K, Neganova I, Moreno-Gimeno I, Al-Aama JY, Burks D, Yung S, Singhapol C, Saretzki G, Evans J, Gorbunova V, Gennery A, Przyborski S, Stojkovic M, Armstrong L, Jeggo P, Lako M (2013) A human iPSC model of Ligase IV deficiency reveals an important role for NHEJ-mediated-DSB repair in the survival and genomic stability of induced pluripotent stem cells and emerging haematopoietic progenitors. Cell Death Differ 20(8):1089–1100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Araki R, Fujimori A, Hamatani K, Mita K, Saito T, Mori M, Fukumura R, Morimyo M, Muto M, Itoh M, Tatsumi K, Abe M (1997) Nonsense mutation at Tyr-4046 in the DNA-dependent protein kinase catalytic subunit of severe combined immune deficiency mice. Proc Natl Acad Sci USA 94(6):2438–2443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Reese JS, Liu L, Gerson SL (2003) Repopulating defect of mismatch repair-deficient hematopoietic stem cells. Blood 102(5):1626–1633

    Article  CAS  PubMed  Google Scholar 

  25. Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, Nomiyama K, Hosokawa K, Sakurada K, Nakagata N, Ikeda Y, Mak TW, Suda T (2004) Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431(7011):997–1002

    Article  CAS  PubMed  Google Scholar 

  26. Prasher JM, Lalai AS, Heijmans-Antonissen C, Ploemacher RE, Hoeijmakers JH, Touw IP, Niedernhofer LJ (2005) Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1−/− mice. EMBO J 24(4):861–871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Navarro S, Meza NW, Quintana-Bustamante O, Casado JA, Jacome A, McAllister K, Puerto S, Surralles J, Segovia JC, Bueren JA (2006) Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1. Mol Ther 14(4):525–535

    Article  CAS  PubMed  Google Scholar 

  28. Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, Rodrigues NP, Crockford TL, Cabuy E, Vindigni A, Enver T, Bell JI, Slijepcevic P, Goodnow CC, Jeggo PA, Cornall RJ (2007) DNA repair is limiting for haematopoietic stem cells during ageing. Nature 447(7145):686–690

    Article  CAS  PubMed  Google Scholar 

  29. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL (2007) Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447(7145):725–729

    Article  CAS  PubMed  Google Scholar 

  30. Takubo K, Ohmura M, Azuma M, Nagamatsu G, Yamada W, Arai F, Hirao A, Suda T (2008) Stem cell defects in ATM-deficient undifferentiated spermatogonia through DNA damage-induced cell-cycle arrest. Cell Stem Cell 2(2):170–182

    Article  CAS  PubMed  Google Scholar 

  31. Zhang QS, Marquez-Loza L, Eaton L, Duncan AW, Goldman DC, Anur P, Watanabe-Smith K, Rathbun RK, Fleming WH, Bagby GC, Grompe M (2010) Fancd2−/− mice have hematopoietic defects that can be partially corrected by resveratrol. Blood 116(24):5140–5148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang S, Yajima H, Huynh H, Zheng J, Callen E, Chen HT, Wong N, Bunting S, Lin YF, Li M, Lee KJ, Story M, Gapud E, Sleckman BP, Nussenzweig A, Zhang CC, Chen DJ, Chen BP (2011) Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair. J Cell Biol 193(2):295–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hoeijmakers JH (2009) DNA damage, aging, and cancer. N Engl J Med 361(15):1475–1485

    Article  CAS  PubMed  Google Scholar 

  34. Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J (2004) Molecular biology of the cell, 5th edn. Freeman, New York, p 963

    Google Scholar 

  35. Challen GA, Little MH (2006) A side order of stem cells: the SP phenotype. Stem Cells 24(1):3–12

    Article  PubMed  Google Scholar 

  36. Tercero JA, Diffley JF (2001) Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint. Nature 412(6846):553–557

    Article  CAS  PubMed  Google Scholar 

  37. Katou Y, Kanoh Y, Bando M, Noguchi H, Tanaka H, Ashikari T, Sugimoto K, Shirahige K (2003) S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex. Nature 424(6952):1078–1083

    Article  CAS  PubMed  Google Scholar 

  38. Pacek M, Tutter AV, Kubota Y, Takisawa H, Walter JC (2006) Localization of MCM2-7, Cdc45, and GINS to the site of DNA unwinding during eukaryotic DNA replication. Mol Cell 21(4):581–587

    Article  CAS  PubMed  Google Scholar 

  39. Bakker ST, Passegue E (2013) Resilient and resourceful: genome maintenance strategies in hematopoietic stem cells. Exp Hematol 41(11):915–923

    Article  CAS  PubMed  Google Scholar 

  40. Savatier P, Lapillonne H, Jirmanova L, Vitelli L, Samarut J (2002) Analysis of the cell cycle in mouse embryonic stem cells. Methods Mol Biol 185:27–33

    CAS  PubMed  Google Scholar 

  41. Kapinas K, Grandy R, Ghule P, Medina R, Becker K, Pardee A, Zaidi SK, Lian J, Stein J, van Wijnen A, Stein G (2013) The abbreviated pluripotent cell cycle. J Cell Physiol 228(1):9–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bernstein C, Prasad AR, Nifonsam V, Bernstein H (2013) DNA damage, DNA repair and cancer. New Research Directions in DNA Repair, pp 1114–1116

  43. Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, Ohmura M, Naka K, Hosokawa K, Ikeda Y, Suda T (2006) Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 12(4):446–451

    Article  CAS  PubMed  Google Scholar 

  44. Jang YY, Sharkis SJ (2007) A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 110(8):3056–3063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yahata T, Takanashi T, Muguruma Y, Ibrahim AA, Matsuzawa H, Uno T, Sheng Y, Onizuka M, Ito M, Kato S, Ando K (2011) Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood 118(11):2941–2950

    Article  CAS  PubMed  Google Scholar 

  46. Greer EL, Brunet A (2005) FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24(50):7410–7425

    Article  CAS  PubMed  Google Scholar 

  47. Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo-Kallanian S, Williams IR, Sears C, Armstrong SA, Passegue E, DePinho RA, Gilliland DG (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128(2):325–339

    Article  CAS  PubMed  Google Scholar 

  48. Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, Matsuoka S, Miyamoto T, Ito K, Ohmura M, Chen C, Hosokawa K, Nakauchi H, Nakayama K, Nakayama KI, Harada M, Motoyama N, Suda T, Hirao A (2007) Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1(1):101–112

    Article  CAS  PubMed  Google Scholar 

  49. Yalcin S, Zhang X, Luciano JP, Mungamuri SK, Marinkovic D, Vercherat C, Sarkar A, Grisotto M, Taneja R, Ghaffari S (2008) Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J Biol Chem 283(37):25692–25705

    Article  CAS  PubMed  Google Scholar 

  50. Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y, Nakao S, Motoyama N, Hirao A (2010) TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463(7281):676–680

    Article  CAS  PubMed  Google Scholar 

  51. Liu J, Cao L, Chen J, Song S, Lee IH, Quijano C, Liu H, Keyvanfar K, Chen H, Cao LY, Ahn BH, Kumar NG, Rovira II, Xu XL, van Lohuizen M, Motoyama N, Deng CX, Finkel T (2009) Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature 459(7245):387–392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD (2007) Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA 104(13):5431–5436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, Shima H, Johnson RS, Hirao A, Suematsu M, Suda T (2010) Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7(3):391–402

    Article  CAS  PubMed  Google Scholar 

  54. Yilmaz OH, Katajisto P, Lamming DW, Gultekin Y, Bauer-Rowe KE, Sengupta S, Birsoy K, Dursun A, Yilmaz VO, Selig M, Nielsen GP, Mino-Kenudson M, Zukerberg LR, Bhan AK, Deshpande V, Sabatini DM (2012) mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486(7404):490–495

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, Joshua B, Kaplan MJ, Wapnir I, Dirbas FM, Somlo G, Garberoglio C, Paz B, Shen J, Lau SK, Quake SR, Brown JM, Weissman IL, Clarke MF (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458(7239):780–783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Studer L, Csete M, Lee SH, Kabbani N, Walikonis J, Wold B, McKay R (2000) Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. J Neurosci 20(19):7377–7383

    CAS  PubMed  Google Scholar 

  57. Chen HL, Pistollato F, Hoeppner DJ, Ni HT, McKay RD, Panchision DM (2007) Oxygen tension regulates survival and fate of mouse central nervous system precursors at multiple levels. Stem Cells 25(9):2291–2301

    Article  PubMed  Google Scholar 

  58. St John JC, Amaral A, Bowles E, Oliveira JF, Lloyd R, Freitas M, Gray HL, Navara CS, Oliveira G, Schatten GP, Spikings E, Ramalho-Santos J (2006) The analysis of mitochondria and mitochondrial DNA in human embryonic stem cells. Methods Mol Biol 331:347–374

    CAS  PubMed  Google Scholar 

  59. Simsek T, Kocabas F, Zheng J, Deberardinis RJ, Mahmoud AI, Olson EN, Schneider JW, Zhang CC, Sadek HA (2010) The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7(3):380–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Prigione A, Fauler B, Lurz R, Lehrach H, Adjaye J (2010) The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells. Stem Cells 28(4):721–733

    Article  CAS  PubMed  Google Scholar 

  61. Mandal S, Lindgren AG, Srivastava AS, Clark AT, Banerjee U (2011) Mitochondrial function controls proliferation and early differentiation potential of embryonic stem cells. Stem Cells 29(3):486–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Le Belle JE, Orozco NM, Paucar AA, Saxe JP, Mottahedeh J, Pyle AD, Wu H, Kornblum HI (2011) Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell 8(1):59–71

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Lamb R, Bonuccelli G, Ozsvari B, Peiris-Pages M, Fiorillo M, Smith DL, Bevilacqua G, Mazzanti CM, McDonnell LA, Naccarato AG, Chiu M, Wynne L, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2015) Mitochondrial mass, a new metabolic biomarker for stem-like cancer cells: understanding WNT/FGF-driven anabolic signaling. Oncotarget 6(31):30453–30471

    PubMed  PubMed Central  Google Scholar 

  64. Farnie G, Sotgia F, Lisanti MP (2015) High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant. Oncotarget 6(31):30472–30486

    PubMed  PubMed Central  Google Scholar 

  65. Saintigny Y, Delacote F, Vares G, Petitot F, Lambert S, Averbeck D, Lopez BS (2001) Characterization of homologous recombination induced by replication inhibition in mammalian cells. EMBO J 20(14):3861–3870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hanada K, Budzowska M, Modesti M, Maas A, Wyman C, Essers J, Kanaar R (2006) The structure-specific endonuclease Mus81-Eme1 promotes conversion of interstrand DNA crosslinks into double-strands breaks. EMBO J 25(20):4921–4932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Rothstein R, Michel B, Gangloff S (2000) Replication fork pausing and recombination or “gimme a break”. Genes Dev 14(1):1–10

    CAS  PubMed  Google Scholar 

  68. Hyrien O (2000) Mechanisms and consequences of replication fork arrest. Biochimie 82(1):5–17

    Article  CAS  PubMed  Google Scholar 

  69. Zou L, Cortez D, Elledge SJ (2002) Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin. Genes Dev 16(2):198–208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300(5625):1542–1548

    Article  CAS  PubMed  Google Scholar 

  71. Zou L, Liu D, Elledge SJ (2003) Replication protein A-mediated recruitment and activation of Rad17 complexes. Proc Natl Acad Sci USA 100(24):13827–13832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wang X, Zou L, Lu T, Bao S, Hurov KE, Hittelman WN, Elledge SJ, Li L (2006) Rad17 phosphorylation is required for claspin recruitment and Chk1 activation in response to replication stress. Mol Cell 23(3):331–341

    Article  PubMed  CAS  Google Scholar 

  73. Lee Y, Katyal S, Downing SM, Zhao J, Russell HR, McKinnon PJ (2012) Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors. Nat Neurosci 15(6):819–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Dronkert ML, Kanaar R (2001) Repair of DNA interstrand cross-links. Mutat Res 486(4):217–247

    Article  CAS  PubMed  Google Scholar 

  75. Gibbs PE, McGregor WG, Maher VM, Nisson P, Lawrence CW (1998) A human homolog of the Saccharomyces cerevisiae REV3 gene, which encodes the catalytic subunit of DNA polymerase zeta. Proc Natl Acad Sci USA 95(12):6876–6880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gibbs PE, Wang XD, Li Z, McManus TP, McGregor WG, Lawrence CW, Maher VM (2000) The function of the human homolog of Saccharomyces cerevisiae REV1 is required for mutagenesis induced by UV light. Proc Natl Acad Sci USA 97(8):4186–4191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yuan F, Zhang Y, Rajpal DK, Wu X, Guo D, Wang M, Taylor JS, Wang Z (2000) Specificity of DNA lesion bypass by the yeast DNA polymerase eta. J Biol Chem 275(11):8233–8239

    Article  CAS  PubMed  Google Scholar 

  78. Srivastava AK, Han C, Zhao R, Cui T, Dai Y, Mao C, Zhao W, Zhang X, Yu J, Wang QE (2015) Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells. Proc Natl Acad Sci USA 112(14):4411–4416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang SC, Nakajima Y, Yu YL, Xia W, Chen CT, Yang CC, McIntush EW, Li LY, Hawke DH, Kobayashi R, Hung MC (2006) Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol 8(12):1359–1368

    Article  CAS  PubMed  Google Scholar 

  80. Bailly V, Lamb J, Sung P, Prakash S, Prakash L (1994) Specific complex formation between yeast RAD6 and RAD18 proteins: a potential mechanism for targeting RAD6 ubiquitin-conjugating activity to DNA damage sites. Genes Dev 8(7):811–820

    Article  CAS  PubMed  Google Scholar 

  81. Bailly V, Lauder S, Prakash S, Prakash L (1997) Yeast DNA repair proteins Rad6 and Rad18 form a heterodimer that has ubiquitin conjugating, DNA binding, and ATP hydrolytic activities. J Biol Chem 272(37):23360–23365

    Article  CAS  PubMed  Google Scholar 

  82. Bailly V, Prakash S, Prakash L (1997) Domains required for dimerization of yeast Rad6 ubiquitin-conjugating enzyme and Rad18 DNA binding protein. Mol Cell Biol 17(8):4536–4543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S (2002) RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419(6903):135–141

    Article  CAS  PubMed  Google Scholar 

  84. Stelter P, Ulrich HD (2003) Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature 425(6954):188–191

    Article  CAS  PubMed  Google Scholar 

  85. Watanabe K, Tateishi S, Kawasuji M, Tsurimoto T, Inoue H, Yamaizumi M (2004) Rad18 guides poleta to replication stalling sites through physical interaction and PCNA monoubiquitination. EMBO J 23(19):3886–3896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Solomon DA, Cardoso MC, Knudsen ES (2004) Dynamic targeting of the replication machinery to sites of DNA damage. J Cell Biol 166(4):455–463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kannouche PL, Wing J, Lehmann AR (2004) Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage. Mol Cell 14(4):491–500

    Article  CAS  PubMed  Google Scholar 

  88. Bienko M, Green CM, Crosetto N, Rudolf F, Zapart G, Coull B, Kannouche P, Wider G, Peter M, Lehmann AR, Hofmann K, Dikic I (2005) Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science 310(5755):1821–1824

    Article  CAS  PubMed  Google Scholar 

  89. Ghosal G, Leung JW, Nair BC, Fong KW, Chen J (2012) Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is a regulator of translesion synthesis. J Biol Chem 287(41):34225–34233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Niimi A, Chambers AL, Downs JA, Lehmann AR (2012) A role for chromatin remodellers in replication of damaged DNA. Nucleic Acids Res 40(15):7393–7403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lorenz A, Osman F, Folkyte V, Sofueva S, Whitby MC (2009) Fbh1 limits Rad51-dependent recombination at blocked replication forks. Mol Cell Biol 29(17):4742–4756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Fugger K, Chu WK, Haahr P, Kousholt AN, Beck H, Payne MJ, Hanada K, Hickson ID, Sorensen CS (2013) FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress. Nat Commun 4:1423

    Article  PubMed  CAS  Google Scholar 

  93. Jeong YT, Rossi M, Cermak L, Saraf A, Florens L, Washburn MP, Sung P, Schildkraut CL, Pagano M (2013) FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress. J Cell Biol 200(2):141–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bacquin A, Pouvelle C, Siaud N, Perderiset M, Salome-Desnoulez S, Tellier-Lebegue C, Lopez B, Charbonnier JB, Kannouche PL (2013) The helicase FBH1 is tightly regulated by PCNA via CRL4(Cdt2)-mediated proteolysis in human cells. Nucleic Acids Res 41(13):6501–6513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Pfander B, Moldovan GL, Sacher M, Hoege C, Jentsch S (2005) SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase. Nature 436(7049):428–433

    CAS  PubMed  Google Scholar 

  96. Moldovan GL, Pfander B, Jentsch S (2006) PCNA controls establishment of sister chromatid cohesion during S phase. Mol Cell 23(5):723–732

    Article  CAS  PubMed  Google Scholar 

  97. Gali H, Juhasz S, Morocz M, Hajdu I, Fatyol K, Szukacsov V, Burkovics P, Haracska L (2012) Role of SUMO modification of human PCNA at stalled replication fork. Nucleic Acids Res 40(13):6049–6059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hofmann RM, Pickart CM (1999) Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 96(5):645–653

    Article  CAS  PubMed  Google Scholar 

  99. Ulrich HD (2003) Protein-protein interactions within an E2-RING finger complex. Implications for ubiquitin-dependent DNA damage repair. J Biol Chem 278(9):7051–7058

    Article  CAS  PubMed  Google Scholar 

  100. Motegi A, Sood R, Moinova H, Markowitz SD, Liu PP, Myung K (2006) Human SHPRH suppresses genomic instability through proliferating cell nuclear antigen polyubiquitination. J Cell Biol 175(5):703–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Unk I, Hajdu I, Fatyol K, Szakal B, Blastyak A, Bermudez V, Hurwitz J, Prakash L, Prakash S, Haracska L (2006) Human SHPRH is a ubiquitin ligase for Mms2-Ubc13-dependent polyubiquitylation of proliferating cell nuclear antigen. Proc Natl Acad Sci USA 103(48):18107–18112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sood R, Makalowska I, Galdzicki M, Hu P, Eddings E, Robbins CM, Moses T, Namkoong J, Chen S, Trent JM (2003) Cloning and characterization of a novel gene, SHPRH, encoding a conserved putative protein with SNF2/helicase and PHD-finger domains from the 6q24 region. Genomics 82(2):153–161

    Article  CAS  PubMed  Google Scholar 

  103. Motegi A, Liaw HJ, Lee KY, Roest HP, Maas A, Wu X, Moinova H, Markowitz SD, Ding H, Hoeijmakers JH, Myung K (2008) Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks. Proc Natl Acad Sci USA 105(34):12411–12416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Unk I, Hajdu I, Fatyol K, Hurwitz J, Yoon JH, Prakash L, Prakash S, Haracska L (2008) Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination. Proc Natl Acad Sci USA 105(10):3768–3773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Motegi A, Kuntz K, Majeed A, Smith S, Myung K (2006) Regulation of gross chromosomal rearrangements by ubiquitin and SUMO ligases in Saccharomyces cerevisiae. Mol Cell Biol 26(4):1424–1433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Haracska L, Torres-Ramos CA, Johnson RE, Prakash S, Prakash L (2004) Opposing effects of ubiquitin conjugation and SUMO modification of PCNA on replicational bypass of DNA lesions in Saccharomyces cerevisiae. Mol Cell Biol 24(10):4267–4274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Johnson RD, Jasin M (2000) Sister chromatid gene conversion is a prominent double-strand break repair pathway in mammalian cells. EMBO J 19(13):3398–3407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lundin C, Erixon K, Arnaudeau C, Schultz N, Jenssen D, Meuth M, Helleday T (2002) Different roles for nonhomologous end joining and homologous recombination following replication arrest in mammalian cells. Mol Cell Biol 22(16):5869–5878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sonoda E, Sasaki MS, Buerstedde JM, Bezzubova O, Shinohara A, Ogawa H, Takata M, Yamaguchi-Iwai Y, Takeda S (1998) Rad51-deficient vertebrate cells accumulate chromosomal breaks prior to cell death. EMBO J 17(2):598–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bolderson E, Scorah J, Helleday T, Smythe C, Meuth M (2004) ATM is required for the cellular response to thymidine induced replication fork stress. Hum Mol Genet 13(23):2937–2945

    Article  CAS  PubMed  Google Scholar 

  111. Saleh-Gohari N, Bryant HE, Schultz N, Parker KM, Cassel TN, Helleday T (2005) Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks. Mol Cell Biol 25(16):7158–7169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wilson DM 3rd, Bohr VA (2007) The mechanics of base excision repair, and its relationship to aging and disease. DNA Repair (Amst) 6(4):544–559

    Article  CAS  Google Scholar 

  113. Maynard S, Swistowska AM, Lee JW, Liu Y, Liu ST, Da Cruz AB, Rao M, de Souza-Pinto NC, Zeng X, Bohr VA (2008) Human embryonic stem cells have enhanced repair of multiple forms of DNA damage. Stem Cells 26(9):2266–2274

    Article  PubMed  PubMed Central  Google Scholar 

  114. Momcilovic O, Knobloch L, Fornsaglio J, Varum S, Easley C, Schatten G (2010) DNA damage responses in human induced pluripotent stem cells and embryonic stem cells. PLoS One 5(10):e13410

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Hildrestrand GA, Diep DB, Kunke D, Bolstad N, Bjoras M, Krauss S, Luna L (2007) The capacity to remove 8-oxoG is enhanced in newborn neural stem/progenitor cells and decreases in juvenile mice and upon cell differentiation. DNA Repair (Amst) 6(6):723–732

    Article  CAS  Google Scholar 

  116. Narciso L, Fortini P, Pajalunga D, Franchitto A, Liu P, Degan P, Frechet M, Demple B, Crescenzi M, Dogliotti E (2007) Terminally differentiated muscle cells are defective in base excision DNA repair and hypersensitive to oxygen injury. Proc Natl Acad Sci USA 104(43):17010–17015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Modrich P (2006) Mechanisms in eukaryotic mismatch repair. J Biol Chem 281(41):30305–30309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Casorelli I, Pelosi E, Biffoni M, Cerio AM, Peschle C, Testa U, Bignami M (2007) Methylation damage response in hematopoietic progenitor cells. DNA Repair (Amst) 6(8):1170–1178

    Article  CAS  Google Scholar 

  119. Lin B, Gupta D, Heinen CD (2014) Human pluripotent stem cells have a novel mismatch repair-dependent damage response. J Biol Chem 289(35):24314–24324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Shuck SC, Short EA, Turchi JJ (2008) Eukaryotic nucleotide excision repair: from understanding mechanisms to influencing biology. Cell Res 18(1):64–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Araujo SJ, Tirode F, Coin F, Pospiech H, Syvaoja JE, Stucki M, Hubscher U, Egly JM, Wood RD (2000) Nucleotide excision repair of DNA with recombinant human proteins: definition of the minimal set of factors, active forms of TFIIH, and modulation by CAK. Genes Dev 14(3):349–359

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Volker M, Mone MJ, Karmakar P, van Hoffen A, Schul W, Vermeulen W, Hoeijmakers JH, van Driel R, van Zeeland AA, Mullenders LH (2001) Sequential assembly of the nucleotide excision repair factors in vivo. Mol Cell 8(1):213–224

    Article  CAS  PubMed  Google Scholar 

  123. Mocquet V, Laine JP, Riedl T, Yajin Z, Lee MY, Egly JM (2008) Sequential recruitment of the repair factors during NER: the role of XPG in initiating the resynthesis step. EMBO J 27(1):155–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Nouspikel T, Hanawalt PC (2000) Terminally differentiated human neurons repair transcribed genes but display attenuated global DNA repair and modulation of repair gene expression. Mol Cell Biol 20(5):1562–1570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Nouspikel T, Hanawalt PC (2006) Impaired nucleotide excision repair upon macrophage differentiation is corrected by E1 ubiquitin-activating enzyme. Proc Natl Acad Sci USA 103(44):16188–16193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Naim V, Rosselli F (2009) The FANC pathway and mitosis: a replication legacy. Cell Cycle 8(18):2907–2911

    Article  CAS  PubMed  Google Scholar 

  127. Soulier J (2011) Fanconi anemia. Hematol Am Soc Hematol Educ Program 2011:492–497

    Article  Google Scholar 

  128. Walden H, Deans AJ (2014) The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder. Annu Rev Biophys 43:257–278

    Article  CAS  PubMed  Google Scholar 

  129. Lu WT, Lemonidis K, Drayton RM, Nouspikel T (2011) The Fanconi anemia pathway is downregulated upon macrophage differentiation through two distinct mechanisms. Cell Cycle 10(19):3300–3310

    Article  CAS  PubMed  Google Scholar 

  130. Huang Y, Li L (2013) DNA crosslinking damage and cancer—a tale of friend and foe. Transl Cancer Res 2(3):144–154

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Essers J, Hendriks RW, Swagemakers SM, Troelstra C, de Wit J, Bootsma D, Hoeijmakers JH, Kanaar R (1997) Disruption of mouse RAD54 reduces ionizing radiation resistance and homologous recombination. Cell 89(2):195–204

    Article  CAS  PubMed  Google Scholar 

  132. Essers J, van Steeg H, de Wit J, Swagemakers SM, Vermeij M, Hoeijmakers JH, Kanaar R (2000) Homologous and non-homologous recombination differentially affect DNA damage repair in mice. EMBO J 19(7):1703–1710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Tichy ED, Pillai R, Deng L, Liang L, Tischfield J, Schwemberger SJ, Babcock GF, Stambrook PJ (2010) Mouse embryonic stem cells, but not somatic cells, predominantly use homologous recombination to repair double-strand DNA breaks. Stem Cells Dev 19(11):1699–1711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Chapman JR, Barral P, Vannier JB, Borel V, Steger M, Tomas-Loba A, Sartori AA, Adams IR, Batista FD, Boulton SJ (2013) RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol Cell 49(5):858–871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zimmermann M, Lottersberger F, Buonomo SB, Sfeir A, de Lange T (2013) 53BP1 regulates DSB repair using Rif1 to control 5′ end resection. Science 339(6120):700–704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Escribano-Diaz C, Orthwein A, Fradet-Turcotte A, Xing M, Young JT, Tkac J, Cook MA, Rosebrock AP, Munro M, Canny MD, Xu D, Durocher D (2013) A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell 49(5):872–883

    Article  CAS  PubMed  Google Scholar 

  137. Di Virgilio M, Callen E, Yamane A, Zhang W, Jankovic M, Gitlin AD, Feldhahn N, Resch W, Oliveira TY, Chait BT, Nussenzweig A, Casellas R, Robbiani DF, Nussenzweig MC (2013) Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science 339(6120):711–715

    Article  PubMed  CAS  Google Scholar 

  138. Mohrin M, Bourke E, Alexander D, Warr MR, Barry-Holson K, Le Beau MM, Morrison CG, Passegue E (2010) Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 7(2):174–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Fan J, Robert C, Jang YY, Liu H, Sharkis S, Baylin SB, Rassool FV (2011) Human induced pluripotent cells resemble embryonic stem cells demonstrating enhanced levels of DNA repair and efficacy of nonhomologous end-joining. Mutat Res 713(1–2):8–17

    Article  CAS  PubMed  Google Scholar 

  140. Sotiropoulou PA, Candi A, Mascre G, De Clercq S, Youssef KK, Lapouge G, Dahl E, Semeraro C, Denecker G, Marine JC, Blanpain C (2010) Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death. Nat Cell Biol 12(6):572–582

    Article  CAS  PubMed  Google Scholar 

  141. de Laval B, Pawlikowska P, Petit-Cocault L, Bilhou-Nabera C, Aubin-Houzelstein G, Souyri M, Pouzoulet F, Gaudry M, Porteu F (2013) Thrombopoietin-increased DNA-PK-dependent DNA repair limits hematopoietic stem and progenitor cell mutagenesis in response to DNA damage. Cell Stem Cell 12(1):37–48

    Article  PubMed  CAS  Google Scholar 

  142. Helleday T (2008) Amplifying tumour-specific replication lesions by DNA repair inhibitors—a new era in targeted cancer therapy. Eur J Cancer 44(7):921–927

    Article  CAS  PubMed  Google Scholar 

  143. Bachrati CZ, Hickson ID (2008) RecQ helicases: guardian angels of the DNA replication fork. Chromosoma 117(3):219–233

    Article  CAS  PubMed  Google Scholar 

  144. Errico A, Costanzo V (2010) Differences in the DNA replication of unicellular eukaryotes and metazoans: known unknowns. EMBO Rep 11(4):270–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Petermann E, Helleday T (2010) Pathways of mammalian replication fork restart. Nat Rev Mol Cell Biol 11(10):683–687

    Article  CAS  PubMed  Google Scholar 

  146. Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP (2006) ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 8(1):37–45

    Article  CAS  PubMed  Google Scholar 

  147. Bianco PR, Tracy RB, Kowalczykowski SC (1998) DNA strand exchange proteins: a biochemical and physical comparison. Front Biosci 3:D570–D603

    CAS  PubMed  Google Scholar 

  148. West SC (2003) Molecular views of recombination proteins and their control. Nat Rev Mol Cell Biol 4(6):435–445

    Article  CAS  PubMed  Google Scholar 

  149. Sung P, Krejci L, Van Komen S, Sehorn MG (2003) Rad51 recombinase and recombination mediators. J Biol Chem 278(44):42729–42732

    Article  CAS  PubMed  Google Scholar 

  150. Rossi MJ, Mazina OM, Bugreev DV, Mazin AV (2011) The RecA/RAD51 protein drives migration of Holliday junctions via polymerization on DNA. Proc Natl Acad Sci USA 108(16):6432–6437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Tarsounas M, Davies D, West SC (2003) BRCA2-dependent and independent formation of RAD51 nuclear foci. Oncogene 22(8):1115–1123

    Article  CAS  PubMed  Google Scholar 

  152. Ouyang KJ, Woo LL, Zhu J, Huo D, Matunis MJ, Ellis NA (2009) SUMO modification regulates BLM and RAD51 interaction at damaged replication forks. PLoS Biol 7(12):e1000252

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Dou H, Huang C, Singh M, Carpenter PB, Yeh ET (2010) Regulation of DNA repair through deSUMOylation and SUMOylation of replication protein A complex. Mol Cell 39(3):333–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Li X, Heyer WD (2008) Homologous recombination in DNA repair and DNA damage tolerance. Cell Res 18(1):99–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Liu N, Lamerdin JE, Tebbs RS, Schild D, Tucker JD, Shen MR, Brookman KW, Siciliano MJ, Walter CA, Fan W, Narayana LS, Zhou ZQ, Adamson AW, Sorensen KJ, Chen DJ, Jones NJ, Thompson LH (1998) XRCC2 and XRCC3, new human Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages. Mol Cell 1(6):783–793

    Article  CAS  PubMed  Google Scholar 

  156. Sonoda E, Zhao GY, Kohzaki M, Dhar PK, Kikuchi K, Redon C, Pilch DR, Bonner WM, Nakano A, Watanabe M, Nakayama T, Takeda S, Takami Y (2007) Collaborative roles of gammaH2AX and the Rad51 paralog Xrcc3 in homologous recombinational repair. DNA Repair (Amst) 6(3):280–292

    Article  CAS  Google Scholar 

  157. Tsuzuki T, Fujii Y, Sakumi K, Tominaga Y, Nakao K, Sekiguchi M, Matsushiro A, Yoshimura Y, Morita T (1996) Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proc Natl Acad Sci USA 93(13):6236–6240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Adams BR, Golding SE, Rao RR, Valerie K (2010) Dynamic dependence on ATR and ATM for double-strand break repair in human embryonic stem cells and neural descendants. PLoS One 5(4):e10001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Tsai RY, McKay RD (2002) A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes Dev 16(23):2991–3003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Baddoo M, Hill K, Wilkinson R, Gaupp D, Hughes C, Kopen GC, Phinney DG (2003) Characterization of mesenchymal stem cells isolated from murine bone marrow by negative selection. J Cell Biochem 89(6):1235–1249

    Article  CAS  PubMed  Google Scholar 

  161. Ohmura M, Naka K, Hoshii T, Muraguchi T, Shugo H, Tamase A, Uema N, Ooshio T, Arai F, Takubo K, Nagamatsu G, Hamaguchi I, Takagi M, Ishihara M, Sakurada K, Miyaji H, Suda T, Hirao A (2008) Identification of stem cells during prepubertal spermatogenesis via monitoring of nucleostemin promoter activity. Stem Cells 26(12):3237–3246

    Article  CAS  PubMed  Google Scholar 

  162. Tamase A, Muraguchi T, Naka K, Tanaka S, Kinoshita M, Hoshii T, Ohmura M, Shugo H, Ooshio T, Nakada M, Sawamoto K, Onodera M, Matsumoto K, Oshima M, Asano M, Saya H, Okano H, Suda T, Hamada J, Hirao A (2009) Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin. Proc Natl Acad Sci USA 106(40):17163–17168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Lin T, Meng L, Li Y, Tsai RY (2010) Tumor-initiating function of nucleostemin-enriched mammary tumor cells. Cancer Res 70(22):9444–9452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Zhu Q, Yasumoto H, Tsai RY (2006) Nucleostemin delays cellular senescence and negatively regulates TRF1 protein stability. Mol Cell Biol 26(24):9279–9290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Beekman C, Nichane M, De Clercq S, Maetens M, Floss T, Wurst W, Bellefroid E, Marine JC (2006) Evolutionarily conserved role of nucleostemin: controlling proliferation of stem/progenitor cells during early vertebrate development. Mol Cell Biol 26(24):9291–9301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Tsai RY (2011) New frontiers in nucleolar research: nucleostemin and related proteins. Nucleolus (Protein Reviews) 15:301–320

    CAS  Google Scholar 

  167. Qu J, Bishop JM (2012) Nucleostemin maintains self-renewal of embryonic stem cells and promotes reprogramming of somatic cells to pluripotency. J Cell Biol 197(6):731–745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Meng L, Lin T, Peng G, Hsu JK, Lee S, Lin S-Y, Tsai RY (2013) Nucleostemin deletion reveals an essential mechanism that maintains the genomic stability of stem and progenitor cells. Proc Natl Acad Sci USA 110(28):11415–11420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Lin T, Ibrahim W, Peng C-Y, Finegold MJ, Tsai RY (2013) A novel role of nucleostemin in maintaining the genome integrity of dividing hepatocytes during mouse liver development and regeneration. Hepatology 58(6):2176–2187

    Article  CAS  PubMed  Google Scholar 

  170. Tsai RY (2015) Pluripotency versus self-renewal of ES cells: two sides of the same coin or more? Stem Cells 33(7):2358–2359

    Article  PubMed  PubMed Central  Google Scholar 

  171. Hsu JK, Lin T, Tsai RY (2012) Nucleostemin prevents telomere damage by promoting PML-IV recruitment to SUMOylated TRF1. J Cell Biol 197(5):613–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Yamashita M, Nitta E, Nagamatsu G, Ikushima YM, Hosokawa K, Arai F, Suda T (2013) Nucleostemin is indispensable for the maintenance and genetic stability of hematopoietic stem cells. Biochem Biophys Res Commun 441(1):196–201

    Article  CAS  PubMed  Google Scholar 

  173. Lin T, Meng L, Wu LJ, Pederson T, Tsai RY (2014) Nucleostemin and GNL3L exercise distinct functions in genome protection and ribosome synthesis, respectively. J Cell Sci 127(10):2302–2312

    Article  CAS  PubMed  Google Scholar 

  174. Tsai RY (2014) Turning a new page on nucleostemin and self-renewal. J Cell Sci 127(18):3885–3891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Tsai RY, Meng L (2009) Nucleostemin: a latecomer with new tricks. Int J Biochem Cell Biol 41(11):2122–2124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Ma H, Pederson T (2007) Depletion of the nucleolar protein nucleostemin causes G1 cell cycle arrest via the p53 pathway. Mol Biol Cell 18(7):2630–2635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Meng L, Lin T, Tsai RY (2008) Nucleoplasmic mobilization of nucleostemin stabilizes MDM2 and promotes G2-M progression and cell survival. J Cell Sci 121(24):4037–4046

    Article  CAS  PubMed  Google Scholar 

  178. Dai MS, Sun XX, Lu H (2008) Aberrant expression of nucleostemin activates p53 and induces cell cycle arrest via inhibition of MDM2. Mol Cell Biol 28(13):4365–4376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Jafarnejad SM, Mowla SJ, Matin MM (2008) Knocking-down the expression of nucleostemin significantly decreases rate of proliferation of rat bone marrow stromal stem cells in an apparently p53-independent manner. Cell Prolif 41(1):28–35

    Article  CAS  PubMed  Google Scholar 

  180. Nikpour P, Mowla SJ, Jafarnejad SM, Fischer U, Schulz WA (2009) Differential effects of Nucleostemin suppression on cell cycle arrest and apoptosis in the bladder cancer cell lines 5637 and SW1710. Cell Prolif 42(6):762–769

    Article  CAS  PubMed  Google Scholar 

  181. Huang G, Meng L, Tsai RY (2015) p53 configures the G2/M arrest response of nucleostemin-deficient cells. Cell Death Discov 1:e15060

    Article  Google Scholar 

  182. Boulton SJ, Jackson SP (1996) Identification of a Saccharomyces cerevisiae Ku80 homologue: roles in DNA double strand break rejoining and in telomeric maintenance. Nucleic Acids Res 24(23):4639–4648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Liang F, Jasin M (1996) Ku80-deficient cells exhibit excess degradation of extrachromosomal DNA. J Biol Chem 271(24):14405–14411

    Article  CAS  PubMed  Google Scholar 

  184. Wilson TE, Grawunder U, Lieber MR (1997) Yeast DNA ligase IV mediates non-homologous DNA end joining. Nature 388(6641):495–498

    Article  CAS  PubMed  Google Scholar 

  185. Kabotyanski EB, Gomelsky L, Han JO, Stamato TD, Roth DB (1998) Double-strand break repair in Ku86- and XRCC4-deficient cells. Nucleic Acids Res 26(23):5333–5342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Lieber MR (2010) The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 79:181–211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Nussenzweig A, Nussenzweig MC (2007) A backup DNA repair pathway moves to the forefront. Cell 131(2):223–225

    Article  CAS  PubMed  Google Scholar 

  188. Corneo B, Wendland RL, Deriano L, Cui X, Klein IA, Wong SY, Arnal S, Holub AJ, Weller GR, Pancake BA, Shah S, Brandt VL, Meek K, Roth DB (2007) Rag mutations reveal robust alternative end joining. Nature 449(7161):483–486

    Article  CAS  PubMed  Google Scholar 

  189. Chayot R, Montagne B, Mazel D, Ricchetti M (2010) An end-joining repair mechanism in Escherichia coli. Proc Natl Acad Sci USA 107(5):2141–2146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Bennardo N, Cheng A, Huang N, Stark JM (2008) Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet 4(6):e1000110

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Perrault R, Wang H, Wang M, Rosidi B, Iliakis G (2004) Backup pathways of NHEJ are suppressed by DNA-PK. J Cell Biochem 92(4):781–794

    Article  CAS  PubMed  Google Scholar 

  192. Peterson SE, Li Y, Chait BT, Gottesman ME, Baer R, Gautier J (2011) Cdk1 uncouples CtIP-dependent resection and Rad51 filament formation during M-phase double-strand break repair. J Cell Biol 194(5):705–720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M, Gumaste S, Geyer M, Zarrin AA, Manis JP, Rajewsky K, Alt FW (2007) IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449(7161):478–482

    Article  CAS  PubMed  Google Scholar 

  194. Simsek D, Jasin M (2010) Alternative end-joining is suppressed by the canonical NHEJ component Xrcc4-ligase IV during chromosomal translocation formation. Nat Struct Mol Biol 17(4):410–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Boboila C, Alt FW, Schwer B (2012) Classical and alternative end-joining pathways for repair of lymphocyte-specific and general DNA double-strand breaks. Adv Immunol 116:1–49

    Article  CAS  PubMed  Google Scholar 

  196. Boulton SJ, Jackson SP (1996) Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways. EMBO J 15(18):5093–5103

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Ma JL, Kim EM, Haber JE, Lee SE (2003) Yeast Mre11 and Rad1 proteins define a Ku-independent mechanism to repair double-strand breaks lacking overlapping end sequences. Mol Cell Biol 23(23):8820–8828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Deriano L, Roth DB (2013) Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage. Annu Rev Genet 47:433–455

    Article  CAS  PubMed  Google Scholar 

  199. Frit P, Barboule N, Yuan Y, Gomez D, Calsou P (2014) Alternative end-joining pathway(s): bricolage at DNA breaks. DNA Repair (Amst) 17:81–97

    Article  CAS  Google Scholar 

  200. Lee K, Lee SE (2007) Saccharomyces cerevisiae Sae2- and Tel1-dependent single-strand DNA formation at DNA break promotes microhomology-mediated end joining. Genetics 176(4):2003–2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Dinkelmann M, Spehalski E, Stoneham T, Buis J, Wu Y, Sekiguchi JM, Ferguson DO (2009) Multiple functions of MRN in end-joining pathways during isotype class switching. Nat Struct Mol Biol 16(8):808–813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Rass E, Grabarz A, Plo I, Gautier J, Bertrand P, Lopez BS (2009) Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells. Nat Struct Mol Biol 16(8):819–824

    Article  CAS  PubMed  Google Scholar 

  203. Xie A, Kwok A, Scully R (2009) Role of mammalian Mre11 in classical and alternative nonhomologous end joining. Nat Struct Mol Biol 16(8):814–818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Zhang Y, Jasin M (2011) An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway. Nat Struct Mol Biol 18(1):80–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Wang M, Wu W, Wu W, Rosidi B, Zhang L, Wang H, Iliakis G (2006) PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res 34(21):6170–6182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Haince JF, McDonald D, Rodrigue A, Dery U, Masson JY, Hendzel MJ, Poirier GG (2008) PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. J Biol Chem 283(2):1197–1208

    Article  CAS  PubMed  Google Scholar 

  207. Robert I, Dantzer F, Reina-San-Martin B (2009) Parp1 facilitates alternative NHEJ, whereas Parp2 suppresses IgH/c-myc translocations during immunoglobulin class switch recombination. J Exp Med 206(5):1047–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Cheng Q, Barboule N, Frit P, Gomez D, Bombarde O, Couderc B, Ren GS, Salles B, Calsou P (2011) Ku counteracts mobilization of PARP1 and MRN in chromatin damaged with DNA double-strand breaks. Nucleic Acids Res 39(22):9605–9619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Sfeir A, de Lange T (2012) Removal of shelterin reveals the telomere end-protection problem. Science 336(6081):593–597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Jia Q, den Dulk-Ras A, Shen H, Hooykaas PJ, de Pater S (2013) Poly(ADP-ribose)polymerases are involved in microhomology mediated back-up non-homologous end joining in Arabidopsis thaliana. Plant Mol Biol 82(4–5):339–351

    Article  CAS  PubMed  Google Scholar 

  211. Villarreal DD, Lee K, Deem A, Shim EY, Malkova A, Lee SE (2012) Microhomology directs diverse DNA break repair pathways and chromosomal translocations. PLoS Genet 8(11):e1003026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Ahmad A, Robinson AR, Duensing A, van Drunen E, Beverloo HB, Weisberg DB, Hasty P, Hoeijmakers JH, Niedernhofer LJ (2008) ERCC1-XPF endonuclease facilitates DNA double-strand break repair. Mol Cell Biol 28(16):5082–5092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Wang H, Rosidi B, Perrault R, Wang M, Zhang L, Windhofer F, Iliakis G (2005) DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. Cancer Res 65(10):4020–4030

    Article  CAS  PubMed  Google Scholar 

  214. Liang L, Deng L, Nguyen SC, Zhao X, Maulion CD, Shao C, Tischfield JA (2008) Human DNA ligases I and III, but not ligase IV, are required for microhomology-mediated end joining of DNA double-strand breaks. Nucleic Acids Res 36(10):3297–3310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Sallmyr A, Tomkinson AE, Rassool FV (2008) Up-regulation of WRN and DNA ligase IIIα in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks. Blood 112(4):1413–1423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Zha S, Boboila C, Alt FW (2009) Mre11: roles in DNA repair beyond homologous recombination. Nat Struct Mol Biol 16(8):798–800

    Article  CAS  PubMed  Google Scholar 

  217. Lee-Theilen M, Matthews AJ, Kelly D, Zheng S, Chaudhuri J (2011) CtIP promotes microhomology-mediated alternative end joining during class-switch recombination. Nat Struct Mol Biol 18(1):75–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Simsek D, Brunet E, Wong SY, Katyal S, Gao Y, McKinnon PJ, Lou J, Zhang L, Li J, Rebar EJ, Gregory PD, Holmes MC, Jasin M (2011) DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation. PLoS Genet 7(6):e1002080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Paul K, Wang M, Mladenov E, Bencsik-Theilen A, Bednar T, Wu W, Arakawa H, Iliakis G (2013) DNA ligases I and III cooperate in alternative non-homologous end-joining in vertebrates. PLoS One 8(3):e59505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. McVey M, Lee SE (2008) MMEJ repair of double-strand breaks (director’s cut): deleted sequences and alternative endings. Trends Genet 24(11):529–538

    Article  CAS  PubMed  Google Scholar 

  221. Truong LN, Li Y, Shi LZ, Hwang PY, He J, Wang H, Razavian N, Berns MW, Wu X (2013) Microhomology-mediated End Joining and Homologous Recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells. Proc Natl Acad Sci USA 110(19):7720–7725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Cairns J (1975) Mutation selection and the natural history of cancer. Nature 255(5505):197–200

    Article  CAS  PubMed  Google Scholar 

  223. Potten CS, Hume WJ, Reid P, Cairns J (1978) The segregation of DNA in epithelial stem cells. Cell 15(3):899–906

    Article  CAS  PubMed  Google Scholar 

  224. Potten CS, Owen G, Booth D (2002) Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci 115(Pt 11):2381–2388

    CAS  PubMed  Google Scholar 

  225. Smith GH (2005) Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands. Development 132(4):681–687

    Article  CAS  PubMed  Google Scholar 

  226. Shinin V, Gayraud-Morel B, Gomes D, Tajbakhsh S (2006) Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nat Cell Biol 8(7):677–687

    Article  CAS  PubMed  Google Scholar 

  227. Conboy MJ, Karasov AO, Rando TA (2007) High incidence of non-random template strand segregation and asymmetric fate determination in dividing stem cells and their progeny. PLoS Biol 5(5):e102

    Article  PubMed  PubMed Central  Google Scholar 

  228. Merok JR, Lansita JA, Tunstead JR, Sherley JL (2002) Cosegregation of chromosomes containing immortal DNA strands in cells that cycle with asymmetric stem cell kinetics. Cancer Res 62(23):6791–6795

    CAS  PubMed  Google Scholar 

  229. Karpowicz P, Morshead C, Kam A, Jervis E, Ramunas J, Cheng V, van der Kooy D (2005) Support for the immortal strand hypothesis: neural stem cells partition DNA asymmetrically in vitro. J Cell Biol 170(5):721–732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Falconer E, Chavez E, Henderson A, Lansdorp PM (2010) Chromosome orientation fluorescence in situ hybridization to study sister chromatid segregation in vivo. Nat Protoc 5(7):1362–1377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Sundararaman B, Avitabile D, Konstandin MH, Cottage CT, Gude N, Sussman MA (2012) Asymmetric chromatid segregation in cardiac progenitor cells is enhanced by Pim-1 kinase. Circ Res 110(9):1169–1173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Tomasetti C, Bozic I (2015) The (not so) immortal strand hypothesis. Stem Cell Res 14(2):238–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Escobar M, Nicolas P, Sangar F, Laurent-Chabalier S, Clair P, Joubert D, Jay P, Legraverend C (2011) Intestinal epithelial stem cells do not protect their genome by asymmetric chromosome segregation. Nat Commun 2:e258

    Article  CAS  Google Scholar 

  234. Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40(2):179–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Marion RM, Strati K, Li H, Murga M, Blanco R, Ortega S, Fernandez-Capetillo O, Serrano M, Blasco MA (2009) A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460(7259):1149–1153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Barlow JL, Drynan LF, Hewett DR, Holmes LR, Lorenzo-Abalde S, Lane AL, Jolin HE, Pannell R, Middleton AJ, Wong SH, Warren AJ, Wainscoat JS, Boultwood J, McKenzie AN (2010) A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome. Nat Med 16(1):59–66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Ceccaldi R, Parmar K, Mouly E, Delord M, Kim JM, Regairaz M, Pla M, Vasquez N, Zhang QS, Pondarre C, Peffault de Latour R, Gluckman E, Cavazzana-Calvo M, Leblanc T, Larghero J, Grompe M, Socie G, D’Andrea AD, Soulier J (2012) Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. Cell Stem Cell 11(1):36–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Zenz T, Eichhorst B, Busch R, Denzel T, Habe S, Winkler D, Buhler A, Edelmann J, Bergmann M, Hopfinger G, Hensel M, Hallek M, Dohner H, Stilgenbauer S (2010) TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol 28(29):4473–4479

    Article  PubMed  Google Scholar 

  239. Zhao Z, Zuber J, Diaz-Flores E, Lintault L, Kogan SC, Shannon K, Lowe SW (2010) p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal. Genes Dev 24(13):1389–1402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Meijne EI, van der Winden-van Groenewegen RJ, Ploemacher RE, Vos O, David JA, Huiskamp R (1991) The effects of x-irradiation on hematopoietic stem cell compartments in the mouse. Exp Hematol 19(7):617–623

    CAS  PubMed  Google Scholar 

  241. Down JD, Boudewijn A, van Os R, Thames HD, Ploemacher RE (1995) Variations in radiation sensitivity and repair among different hematopoietic stem cell subsets following fractionated irradiation. Blood 86(1):122–127

    CAS  PubMed  Google Scholar 

  242. Song S, Lambert PF (1999) Different responses of epidermal and hair follicular cells to radiation correlate with distinct patterns of p53 and p21 induction. Am J Pathol 155(4):1121–1127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Merritt AJ, Potten CS, Kemp CJ, Hickman JA, Balmain A, Lane DP, Hall PA (1994) The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. Cancer Res 54(3):614–617

    CAS  PubMed  Google Scholar 

  244. Merritt AJ, Potten CS, Watson AJ, Loh DY, Nakayama K, Nakayama K, Hickman JA (1995) Differential expression of bcl-2 in intestinal epithelia. Correlation with attenuation of apoptosis in colonic crypts and the incidence of colonic neoplasia. J Cell Sci 108(Pt 6):2261–2271

    CAS  PubMed  Google Scholar 

  245. Milyavsky M, Gan OI, Trottier M, Komosa M, Tabach O, Notta F, Lechman E, Hermans KG, Eppert K, Konovalova Z, Ornatsky O, Domany E, Meyn MS, Dick JE (2010) A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal. Cell Stem Cell 7(2):186–197

    Article  CAS  PubMed  Google Scholar 

  246. Warr MR, Binnewies M, Flach J, Reynaud D, Garg T, Malhotra R, Debnath J, Passegue E (2013) FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494(7437):323–327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Rodolfo C, Di Bartolomeo S, Cecconi F (2015) Autophagy in stem and progenitor cells. Cell Mol Life Sci (Epub ahead of print)

  248. Owusu-Ansah E, Banerjee U (2009) Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461(7263):537–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Inomata K, Aoto T, Binh NT, Okamoto N, Tanimura S, Wakayama T, Iseki S, Hara E, Masunaga T, Shimizu H, Nishimura EK (2009) Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell 137(6):1088–1099

    Article  CAS  PubMed  Google Scholar 

  250. Wang J, Sun Q, Morita Y, Jiang H, Gross A, Lechel A, Hildner K, Guachalla LM, Gompf A, Hartmann D, Schambach A, Wuestefeld T, Dauch D, Schrezenmeier H, Hofmann WK, Nakauchi H, Ju Z, Kestler HA, Zender L, Rudolph KL (2012) A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage. Cell 148(5):1001–1014

    Article  CAS  PubMed  Google Scholar 

  251. Granger MP, Wright WE, Shay JW (2002) Telomerase in cancer and aging. Crit Rev Oncol Hematol 41(1):29–40

    Article  PubMed  Google Scholar 

  252. Kim Sh SH, Kaminker P, Campisi J (2002) Telomeres, aging and cancer: in search of a happy ending. Oncogene 21(4):503–511

    Article  PubMed  Google Scholar 

  253. Wong JM, Collins K (2003) Telomere maintenance and disease. Lancet 362(9388):983–988

    Article  CAS  PubMed  Google Scholar 

  254. Feldser DM, Hackett JA, Greider CW (2003) Telomere dysfunction and the initiation of genome instability. Nat Rev Cancer 3(8):623–627

    Article  CAS  PubMed  Google Scholar 

  255. Blasco MA (2005) Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 6(8):611–622

    Article  CAS  PubMed  Google Scholar 

  256. Greider CW, Blackburn EH (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43(2 Pt 1):405–413

    Article  CAS  PubMed  Google Scholar 

  257. Shay JW, Zou Y, Hiyama E, Wright WE (2001) Telomerase and cancer. Hum Mol Genet 10(7):677–685

    Article  CAS  PubMed  Google Scholar 

  258. Allsopp RC, Morin GB, DePinho R, Harley CB, Weissman IL (2003) Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 102(2):517–520

    Article  CAS  PubMed  Google Scholar 

  259. Yeager TR, Neumann AA, Englezou A, Huschtscha LI, Noble JR, Reddel RR (1999) Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. Cancer Res 59(17):4175–4179

    CAS  PubMed  Google Scholar 

  260. Dunham MA, Neumann AA, Fasching CL, Reddel RR (2000) Telomere maintenance by recombination in human cells. Nat Genet 26(4):447–450

    Article  CAS  PubMed  Google Scholar 

  261. Fasching CL, Neumann AA, Muntoni A, Yeager TR, Reddel RR (2007) DNA damage induces alternative lengthening of telomeres (ALT) associated promyelocytic leukemia bodies that preferentially associate with linear telomeric DNA. Cancer Res 67(15):7072–7077

    Article  CAS  PubMed  Google Scholar 

  262. Grobelny JV, Godwin AK, Broccoli D (2000) ALT-associated PML bodies are present in viable cells and are enriched in cells in the G(2)/M phase of the cell cycle. J Cell Sci 113(Pt 24):4577–4585

    CAS  PubMed  Google Scholar 

  263. Wu G, Lee WH, Chen PL (2000) NBS1 and TRF1 colocalize at promyelocytic leukemia bodies during late S/G2 phases in immortalized telomerase-negative cells. Implication of NBS1 in alternative lengthening of telomeres. J Biol Chem 275(39):30618–30622

    Article  CAS  PubMed  Google Scholar 

  264. Wu G, Jiang X, Lee WH, Chen PL (2003) Assembly of functional ALT-associated promyelocytic leukemia bodies requires Nijmegen Breakage Syndrome 1. Cancer Res 63(10):2589–2595

    CAS  PubMed  Google Scholar 

  265. Nabetani A, Yokoyama O, Ishikawa F (2004) Localization of hRad9, hHus1, hRad1, and hRad17 and caffeine-sensitive DNA replication at the alternative lengthening of telomeres-associated promyelocytic leukemia body. J Biol Chem 279(24):25849–25857

    Article  CAS  PubMed  Google Scholar 

  266. Liu L, Bailey SM, Okuka M, Munoz P, Li C, Zhou L, Wu C, Czerwiec E, Sandler L, Seyfang A, Blasco MA, Keefe DL (2007) Telomere lengthening early in development. Nat Cell Biol 9(12):1436–1441

    Article  CAS  PubMed  Google Scholar 

  267. Bechter OE, Zou Y, Walker W, Wright WE, Shay JW (2004) Telomeric recombination in mismatch repair deficient human colon cancer cells after telomerase inhibition. Cancer Res 64(10):3444–3451

    Article  CAS  PubMed  Google Scholar 

  268. Hu J, Hwang SS, Liesa M, Gan B, Sahin E, Jaskelioff M, Ding Z, Ying H, Boutin AT, Zhang H, Johnson S, Ivanova E, Kost-Alimova M, Protopopov A, Wang YA, Shirihai OS, Chin L, Depinho RA (2012) Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Cell 148(4):651–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Oganesian L, Karlseder J (2011) Mammalian 5′ C-rich telomeric overhangs are a mark of recombination-dependent telomere maintenance. Mol Cell 42(2):224–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S, Offerhaus GJ, McLendon R, Rasheed BA, He Y, Yan H, Bigner DD, Oba-Shinjo SM, Marie SK, Riggins GJ, Kinzler KW, Vogelstein B, Hruban RH, Maitra A, Papadopoulos N, Meeker AK (2011) Altered telomeres in tumors with ATRX and DAXX mutations. Science 333(6041):425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tonjes M, Hovestadt V, Albrecht S, Kool M, Nantel A, Konermann C, Lindroth A, Jager N, Rausch T, Ryzhova M, Korbel JO, Hielscher T, Hauser P, Garami M, Klekner A, Bognar L, Ebinger M, Schuhmann MU, Scheurlen W, Pekrun A, Fruhwald MC, Roggendorf W, Kramm C, Durken M, Atkinson J, Lepage P, Montpetit A, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel P, Kulozik AE, Zapatka M, Guha A, Malkin D, Felsberg J, Reifenberger G, von Deimling A, Ichimura K, Collins VP, Witt H, Milde T, Witt O, Zhang C, Castelo-Branco P, Lichter P, Faury D, Tabori U, Plass C, Majewski J, Pfister SM, Jabado N (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482(7384):226–231

    Article  CAS  PubMed  Google Scholar 

  272. Bower K, Napier CE, Cole SL, Dagg RA, Lau LM, Duncan EL, Moy EL, Reddel RR (2012) Loss of wild-type ATRX expression in somatic cell hybrids segregates with activation of alternative lengthening of telomeres. PLoS One 7(11):e50062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Due to the scope of the reviewed subject, all studies as relevant and deserving as those cited may not be exhaustively enlisted in this article. R.Y.T. is in part supported by NCI-PHS Grant R03 CA201988.

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  1. Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, 2121 W. Holcombe Blvd, Houston, TX, 77030, USA

    Robert Y. L. Tsai

  2. Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, TX, 77843, USA

    Robert Y. L. Tsai

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Tsai, R.Y.L. Balancing self-renewal against genome preservation in stem cells: How do they manage to have the cake and eat it too?. Cell. Mol. Life Sci. 73, 1803–1823 (2016). https://doi.org/10.1007/s00018-016-2152-y

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  • DOI: https://doi.org/10.1007/s00018-016-2152-y

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