Cellular and Molecular Life Sciences

, Volume 71, Issue 23, pp 4507–4517 | Cite as

Replication fork recovery and regulation of common fragile sites stability

Multi-author review

Abstract

The acquisition of genomic instability is a triggering factor in cancer development, and common fragile sites (CFS) are the preferential target of chromosomal instability under conditions of replicative stress in the human genome. Although the mechanisms leading to CFS expression and the cellular factors required to suppress CFS instability remain largely undefined, it is clear that DNA becomes more susceptible to breakage when replication is impaired. The models proposed so far to explain how CFS instability arises imply that replication fork progression along these regions is perturbed due to intrinsic features of fragile sites and events that directly affect DNA replication. The observation that proteins implicated in the safe recovery of stalled forks or in engaging recombination at collapsed forks increase CFS expression when downregulated or mutated suggests that the stabilization and recovery of perturbed replication forks are crucial to guarantee CFS integrity.

Keywords

Genome instability Replication fork arrest Replication checkpoint Werner syndrome protein Common fragile sites 

References

  1. 1.
    Glover TW, Berger C, Coyle J, Echo B (1984) DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum Genet 67(2):136–142PubMedCrossRefGoogle Scholar
  2. 2.
    Glover TW, Arlt MF, Casper AM, Durkin SG (2005) Mechanisms of common fragile site instability. Hum Mol Genet 14 Spec No. 2:R197–R205. doi:10.1093/hmg/ddi265 PubMedCrossRefGoogle Scholar
  3. 3.
    Hecht F, Glover TW (1984) Cancer chromosome breakpoints and common fragile sites induced by aphidicolin. Cancer Genet Cytogenet 13(2):185–188 (0165-4608(84)90060-8 [pii])PubMedCrossRefGoogle Scholar
  4. 4.
    Mangelsdorf M, Ried K, Woollatt E, Dayan S, Eyre H, Finnis M, Hobson L, Nancarrow J, Venter D, Baker E, Richards RI (2000) Chromosomal fragile site FRA16D and DNA instability in cancer. Cancer Res 60(6):1683–1689PubMedGoogle Scholar
  5. 5.
    Mimori K, Druck T, Inoue H, Alder H, Berk L, Mori M, Huebner K, Croce CM (1999) Cancer-specific chromosome alterations in the constitutive fragile region FRA3B. Proc Natl Acad Sci USA 96(13):7456–7461PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Yunis JJ, Soreng AL (1984) Constitutive fragile sites and cancer. Science 226(4679):1199–1204PubMedCrossRefGoogle Scholar
  7. 7.
    Branzei D, Foiani M (2009) The checkpoint response to replication stress. DNA Repair (Amst) 8(9):1038–1046. doi:10.1016/j.dnarep.2009.04.014 CrossRefGoogle Scholar
  8. 8.
    Debatisse M, Le Tallec B, Letessier A, Dutrillaux B, Brison O (2012) Common fragile sites: mechanisms of instability revisited. Trends Genet 28(1):22–32. doi:10.1016/j.tig.2011.10.003 PubMedCrossRefGoogle Scholar
  9. 9.
    Durkin SG, Glover TW (2007) Chromosome fragile sites. Annu Rev Genet 41:169–192PubMedCrossRefGoogle Scholar
  10. 10.
    Lukusa T, Fryns JP (2008) Human chromosome fragility. Biochim Biophys Acta 1779(1):3–16. doi:10.1016/j.bbagrm.2007.10.005 PubMedCrossRefGoogle Scholar
  11. 11.
    Le Tallec B, Dutrillaux B, Lachages AM, Millot GA, Brison O, Debatisse M (2011) Molecular profiling of common fragile sites in human fibroblasts. Nat Struct Mol Biol 18(12):1421–1423. doi:10.1038/nsmb.2155 PubMedCrossRefGoogle Scholar
  12. 12.
    Letessier A, Millot GA, Koundrioukoff S, Lachages AM, Vogt N, Hansen RS, Malfoy B, Brison O, Debatisse M (2011) Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature 470(7332):120–123. doi:10.1038/nature09745 PubMedCrossRefGoogle Scholar
  13. 13.
    Mishmar D, Rahat A, Scherer SW, Nyakatura G, Hinzmann B, Kohwi Y, Mandel-Gutfroind Y, Lee JR, Drescher B, Sas DE, Margalit H, Platzer M, Weiss A, Tsui LC, Rosenthal A, Kerem B (1998) Molecular characterization of a common fragile site (FRA7H) on human chromosome 7 by the cloning of a simian virus 40 integration site. Proc Natl Acad Sci USA 95(14):8141–8146PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Zlotorynski E, Rahat A, Skaug J, Ben-Porat N, Ozeri E, Hershberg R, Levi A, Scherer SW, Margalit H, Kerem B (2003) Molecular basis for expression of common and rare fragile sites. Mol Cell Biol 23(20):7143–7151PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Zhang H, Freudenreich CH (2007) An AT-rich sequence in human common fragile site FRA16D causes fork stalling and chromosome breakage in S. cerevisiae. Mol Cell 27(3):367–379. doi:10.1016/j.molcel.2007.06.012 PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Ragland RL, Glynn MW, Arlt MF, Glover TW (2008) Stably transfected common fragile site sequences exhibit instability at ectopic sites. Genes Chromosomes Cancer 47(10):860–872. doi:10.1002/gcc.20591 PubMedCrossRefGoogle Scholar
  17. 17.
    Burrow AA, Marullo A, Holder LR, Wang YH (2010) Secondary structure formation and DNA instability at fragile site FRA16B. Nucleic Acids Res 38(9):2865–2877. doi:10.1093/nar/gkp1245 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Ozeri-Galai E, Bester AC, Kerem B (2012) The complex basis underlying common fragile site instability in cancer. Trends Genet 28(6):295–302. doi:10.1016/j.tig.2012.02.006 PubMedCrossRefGoogle Scholar
  19. 19.
    Palumbo E, Matricardi L, Tosoni E, Bensimon A, Russo A (2010) Replication dynamics at common fragile site FRA6E. Chromosoma 119(6):575–587. doi:10.1007/s00412-010-0279-4 PubMedCrossRefGoogle Scholar
  20. 20.
    Helmrich A, Ballarino M, Tora L (2011) Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol Cell 44(6):966–977. doi:10.1016/j.molcel.2011.10.013 PubMedCrossRefGoogle Scholar
  21. 21.
    Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C, Orntoft T, Lukas J, Bartek J (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434(7035):864–870PubMedCrossRefGoogle Scholar
  22. 22.
    Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, Venere M, Ditullio RA Jr, Kastrinakis NG, Levy B, Kletsas D, Yoneta A, Herlyn M, Kittas C, Halazonetis TD (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434(7035):907–913PubMedCrossRefGoogle Scholar
  23. 23.
    Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15(17):2177–2196PubMedCrossRefGoogle Scholar
  24. 24.
    Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300(5625):1542–1548PubMedCrossRefGoogle Scholar
  25. 25.
    Budzowska M, Kanaar R (2009) Mechanisms of dealing with DNA damage-induced replication problems. Cell Biochem Biophys 53(1):17–31PubMedCrossRefGoogle Scholar
  26. 26.
    Casper AM, Durkin SG, Arlt MF, Glover TW (2004) Chromosomal instability at common fragile sites in Seckel syndrome. Am J Hum Genet 75(4):654–660. doi:10.1086/422701 PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Casper AM, Nghiem P, Arlt MF, Glover TW (2002) ATR regulates fragile site stability. Cell 111(6):779–789PubMedCrossRefGoogle Scholar
  28. 28.
    Cha RS, Kleckner N (2002) ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones. Science 297(5581):602–606. doi:10.1126/science.1071398 PubMedCrossRefGoogle Scholar
  29. 29.
    Dillon LW, Burrow AA, Wang YH (2010) DNA instability at chromosomal fragile sites in cancer. Curr Genomics 11(5):326–337. doi:10.2174/138920210791616699 PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Franchitto A, Pichierri P (2011) Understanding the molecular basis of common fragile sites instability: role of the proteins involved in the recovery of stalled replication forks. Cell Cycle 10(23):4039–4046. doi:10.4161/cc.10.23.18409 PubMedCrossRefGoogle Scholar
  31. 31.
    Zhao H, Piwnica-Worms H (2001) ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol 21(13):4129–4139. doi:10.1128/MCB.21.13.4129-4139.2001 PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Lopes M, Cotta-Ramusino C, Pellicioli A, Liberi G, Plevani P, Muzi-Falconi M, Newlon CS, Foiani M (2001) The DNA replication checkpoint response stabilizes stalled replication forks. Nature 412(6846):557–561. doi:10.1038/35087613 PubMedCrossRefGoogle Scholar
  33. 33.
    Maya-Mendoza A, Petermann E, Gillespie DA, Caldecott KW, Jackson DA (2007) Chk1 regulates the density of active replication origins during the vertebrate S phase. EMBO J 26(11):2719–2731. doi:10.1038/sj.emboj.7601714 PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Petermann E, Caldecott KW (2006) Evidence that the ATR/Chk1 pathway maintains normal replication fork progression during unperturbed S phase. Cell Cycle 5(19):2203–2209 (3256 [pii])PubMedCrossRefGoogle Scholar
  35. 35.
    Syljuasen RG, Sorensen CS, Hansen LT, Fugger K, Lundin C, Johansson F, Helleday T, Sehested M, Lukas J, Bartek J (2005) Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakage. Mol Cell Biol 25(9):3553–3562. doi:10.1128/MCB.25.9.3553-3562.2005 PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Durkin SG, Arlt MF, Howlett NG, Glover TW (2006) Depletion of CHK1, but not CHK2, induces chromosomal instability and breaks at common fragile sites. Oncogene 25(32):4381–4388PubMedCrossRefGoogle Scholar
  37. 37.
    Focarelli ML, Soza S, Mannini L, Paulis M, Montecucco A, Musio A (2009) Claspin inhibition leads to fragile site expression. Genes Chromosomes Cancer 48(12):1083–1090. doi:10.1002/gcc.20710 PubMedCrossRefGoogle Scholar
  38. 38.
    Zhu M, Weiss RS (2007) Increased common fragile site expression, cell proliferation defects, and apoptosis following conditional inactivation of mouse Hus1 in primary cultured cells. Mol Biol Cell 18(3):1044–1055PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    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. doi:10.1038/nature01900 PubMedCrossRefGoogle Scholar
  40. 40.
    Dang T, Bao S, Wang XF (2005) Human Rad9 is required for the activation of S-phase checkpoint and the maintenance of chromosomal stability. Genes Cells 10(4):287–295. doi:10.1111/j.1365-2443.2005.00840.x PubMedCrossRefGoogle Scholar
  41. 41.
    Musio A, Montagna C, Mariani T, Tilenni M, Focarelli ML, Brait L, Indino E, Benedetti PA, Chessa L, Albertini A, Ried T, Vezzoni P (2005) SMC1 involvement in fragile site expression. Hum Mol Genet 14(4):525–533. doi:10.1093/hmg/ddi049 PubMedCrossRefGoogle Scholar
  42. 42.
    Akhmedov AT, Frei C, Tsai-Pflugfelder M, Kemper B, Gasser SM, Jessberger R (1998) Structural maintenance of chromosomes protein C-terminal domains bind preferentially to DNA with secondary structure. J Biol Chem 273(37):24088–24094PubMedCrossRefGoogle Scholar
  43. 43.
    Ammazzalorso F, Pirzio LM, Bignami M, Franchitto A, Pichierri P (2010) ATR and ATM differently regulate WRN to prevent DSBs at stalled replication forks and promote replication fork recovery. EMBO J 29(18):3156–3169. doi:10.1038/emboj.2010.205 PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Otterlei M, Bruheim P, Ahn B, Bussen W, Karmakar P, Baynton K, Bohr VA (2006) Werner syndrome protein participates in a complex with RAD51, RAD54, RAD54B and ATR in response to ICL-induced replication arrest. J Cell Sci 119(Pt 24):5137–5146. doi:10.1242/jcs.03291 PubMedCrossRefGoogle Scholar
  45. 45.
    Pichierri P, Rosselli F, Franchitto A (2003) Werner’s syndrome protein is phosphorylated in an ATR/ATM-dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle. Oncogene 22(10):1491–1500PubMedCrossRefGoogle Scholar
  46. 46.
    Baynton K, Otterlei M, Bjoras M, von Kobbe C, Bohr VA, Seeberg E (2003) WRN interacts physically and functionally with the recombination mediator protein RAD52. J Biol Chem 278(38):36476–36486. doi:10.1074/jbc.M303885200 PubMedCrossRefGoogle Scholar
  47. 47.
    Pichierri P, Franchitto A, Mosesso P, Palitti F (2001) Werner’s syndrome protein is required for correct recovery after replication arrest and DNA damage induced in S-phase of cell cycle. Mol Biol Cell 12(8):2412–2421PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Sakamoto S, Nishikawa K, Heo SJ, Goto M, Furuichi Y, Shimamoto A (2001) Werner helicase relocates into nuclear foci in response to DNA damaging agents and co-localizes with RPA and Rad51. Genes Cells 6(5):421–430 (gtc433 [pii])PubMedCrossRefGoogle Scholar
  49. 49.
    Pirzio LM, Pichierri P, Bignami M, Franchitto A (2008) Werner syndrome helicase activity is essential in maintaining fragile site stability. J Cell Biol 180(2):305–314PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Heller RC, Marians KJ (2005) The disposition of nascent strands at stalled replication forks dictates the pathway of replisome loading during restart. Mol Cell 17(5):733–743. doi:10.1016/j.molcel.2005.01.019 PubMedCrossRefGoogle Scholar
  51. 51.
    Heller RC, Marians KJ (2006) Replication fork reactivation downstream of a blocked nascent leading strand. Nature 439(7076):557–562. doi:10.1038/nature04329 PubMedCrossRefGoogle Scholar
  52. 52.
    Van C, Yan S, Michael WM, Waga S, Cimprich KA (2010) Continued primer synthesis at stalled replication forks contributes to checkpoint activation. J Cell Biol 189(2):233–246. doi:10.1083/jcb.200909105 PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Miotto B, Chibi M, Xie P, Koundrioukoff S, Moolman-Smook H, Pugh D, Debatisse M, He F, Zhang L, Defossez PA (2014) The RBBP6/ZBTB38/MCM10 axis regulates DNA replication and common fragile site stability. Cell Rep 7(2):575–587. doi:10.1016/j.celrep.2014.03.030 PubMedCrossRefGoogle Scholar
  54. 54.
    Zhu W, Ukomadu C, Jha S, Senga T, Dhar SK, Wohlschlegel JA, Nutt LK, Kornbluth S, Dutta A (2007) Mcm10 and And-1/CTF4 recruit DNA polymerase alpha to chromatin for initiation of DNA replication. Genes Dev 21(18):2288–2299. doi:10.1101/gad.1585607 PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Murfuni I, De Santis A, Federico M, Bignami M, Pichierri P, Franchitto A (2012) Perturbed replication induced genome wide or at common fragile sites is differently managed in the absence of WRN. Carcinogenesis 33(9):1655–1663. doi:10.1093/carcin/bgs206 PubMedCrossRefGoogle Scholar
  56. 56.
    Petermann E, Woodcock M, Helleday T (2010) Chk1 promotes replication fork progression by controlling replication initiation. Proc Natl Acad Sci USA 107(37):16090–16095. doi:10.1073/pnas.1005031107 PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Singleton MR, Scaife S, Wigley DB (2001) Structural analysis of DNA replication fork reversal by RecG. Cell 107(1):79–89 (S0092-8674(01)00501-3 [pii])PubMedCrossRefGoogle Scholar
  58. 58.
    Whitby MC, Vincent SD, Lloyd RG (1994) Branch migration of Holliday junctions: identification of RecG protein as a junction specific DNA helicase. EMBO J 13(21):5220–5228PubMedCentralPubMedGoogle Scholar
  59. 59.
    Sogo JM, Lopes M, Foiani M (2002) Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects. Science 297(5581):599–602. doi:10.1126/science.1074023 PubMedCrossRefGoogle Scholar
  60. 60.
    Ray Chaudhuri A, Hashimoto Y, Herrador R, Neelsen KJ, Fachinetti D, Bermejo R, Cocito A, Costanzo V, Lopes M (2012) Topoisomerase I poisoning results in PARP-mediated replication fork reversal. Nat Struct Mol Biol 19(4):417–423. doi:10.1038/nsmb.2258 PubMedCrossRefGoogle Scholar
  61. 61.
    Betous R, Mason AC, Rambo RP, Bansbach CE, Badu-Nkansah A, Sirbu BM, Eichman BF, Cortez D (2012) SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication. Genes Dev 26(2):151–162. doi:10.1101/gad.178459.111 PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Ciccia A, Nimonkar AV, Hu Y, Hajdu I, Achar YJ, Izhar L, Petit SA, Adamson B, Yoon JC, Kowalczykowski SC, Livingston DM, Haracska L, Elledge SJ (2012) Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress. Mol Cell 47(3):396–409. doi:10.1016/j.molcel.2012.05.024 PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Gari K, Decaillet C, Stasiak AZ, Stasiak A, Constantinou A (2008) The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks. Mol Cell 29(1):141–148. doi:10.1016/j.molcel.2007.11.032 PubMedCrossRefGoogle Scholar
  64. 64.
    Machwe A, Xiao L, Groden J, Orren DK (2006) The Werner and Bloom syndrome proteins catalyze regression of a model replication fork. Biochemistry 45(47):13939–13946. doi:10.1021/bi0615487 PubMedCrossRefGoogle Scholar
  65. 65.
    Betous R, Couch FB, Mason AC, Eichman BF, Manosas M, Cortez D (2013) Substrate-selective repair and restart of replication forks by DNA translocases. Cell Rep 3(6):1958–1969. doi:10.1016/j.celrep.2013.05.002 PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Berti M, Ray Chaudhuri A, Thangavel S, Gomathinayagam S, Kenig S, Vujanovic M, Odreman F, Glatter T, Graziano S, Mendoza-Maldonado R, Marino F, Lucic B, Biasin V, Gstaiger M, Aebersold R, Sidorova JM, Monnat RJ Jr, Lopes M, Vindigni A (2013) Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat Struct Mol Biol 20(3):347–354. doi:10.1038/nsmb.2501 PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Bansbach CE, Betous R, Lovejoy CA, Glick GG, Cortez D (2009) The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks. Genes Dev 23(20):2405–2414. doi:10.1101/gad.1839909 PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Betous R, Glick GG, Zhao R, Cortez D (2013) Identification and characterization of SMARCAL1 protein complexes. PLoS ONE 8(5):e63149. doi:10.1371/journal.pone.0063149 PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Cotta-Ramusino C, Fachinetti D, Lucca C, Doksani Y, Lopes M, Sogo J, Foiani M (2005) Exo1 processes stalled replication forks and counteracts fork reversal in checkpoint-defective cells. Mol Cell 17(1):153–159. doi:10.1016/j.molcel.2004.11.032 PubMedCrossRefGoogle Scholar
  70. 70.
    Hashimoto Y, Ray Chaudhuri A, Lopes M, Costanzo V (2010) Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis. Nat Struct Mol Biol 17(11):1305–1311. doi:10.1038/nsmb.1927 PubMedCrossRefGoogle Scholar
  71. 71.
    Schlacher K, Christ N, Siaud N, Egashira A, Wu H, Jasin M (2011) Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145(4):529–542. doi:10.1016/j.cell.2011.03.041 PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Machwe A, Karale R, Xu X, Liu Y, Orren DK (2011) The Werner and Bloom syndrome proteins help resolve replication blockage by converting (regressed) holliday junctions to functional replication forks. Biochemistry 50(32):6774–6788. doi:10.1021/bi2001054 PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Franchitto A, Pichierri P (2004) Werner syndrome protein and the MRE11 complex are involved in a common pathway of replication fork recovery. Cell Cycle 3(10):1331–1339 (1185 [pii])PubMedCrossRefGoogle Scholar
  74. 74.
    Lu X, Parvathaneni S, Hara T, Lal A, Sharma S (2013) Replication stress induces specific enrichment of RECQ1 at common fragile sites FRA3B and FRA16D. Mol Cancer 12(1):29. doi:10.1186/1476-4598-12-29 PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Llorente B, Smith CE, Symington LS (2008) Break-induced replication: what is it and what is it for? Cell Cycle 7(7):859–864 (5613 [pii])PubMedCrossRefGoogle Scholar
  76. 76.
    Malkova A, Ira G (2013) Break-induced replication: functions and molecular mechanism. Curr Opin Genet Dev 23(3):271–279. doi:10.1016/j.gde.2013.05.007 PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Hashimoto Y, Puddu F, Costanzo V (2012) RAD51- and MRE11-dependent reassembly of uncoupled CMG helicase complex at collapsed replication forks. Nat Struct Mol Biol 19(1):17–24. doi:10.1038/nsmb.2177 CrossRefGoogle Scholar
  78. 78.
    Murfuni I, Basile G, Subramanyam S, Malacaria E, Bignami M, Spies M, Franchitto A, Pichierri P (2013) Survival of the replication checkpoint deficient cells requires MUS81-RAD52 function. PLoS Genet 9(10):e1003910. doi:10.1371/journal.pgen.1003910 PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Deem A, Keszthelyi A, Blackgrove T, Vayl A, Coffey B, Mathur R, Chabes A, Malkova A (2011) Break-induced replication is highly inaccurate. PLoS Biol 9(2):e1000594. doi:10.1371/journal.pbio.1000594 PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Hicks JK, Chute CL, Paulsen MT, Ragland RL, Howlett NG, Gueranger Q, Glover TW, Canman CE (2010) Differential roles for DNA polymerases eta, zeta, and REV1 in lesion bypass of intrastrand versus interstrand DNA cross-links. Mol Cell Biol 30(5):1217–1230. doi:10.1128/MCB.00993-09 PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Mizuno K, Miyabe I, Schalbetter SA, Carr AM, Murray JM (2013) Recombination-restarted replication makes inverted chromosome fusions at inverted repeats. Nature 493(7431):246–249. doi:10.1038/nature11676 PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Naim V, Wilhelm T, Debatisse M, Rosselli F (2013) ERCC1 and MUS81-EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis. Nat Cell Biol 15(8):1008–1015. doi:10.1038/ncb2793 PubMedCrossRefGoogle Scholar
  83. 83.
    Ying S, Minocherhomji S, Chan KL, Palmai-Pallag T, Chu WK, Wass T, Mankouri HW, Liu Y, Hickson ID (2013) MUS81 promotes common fragile site expression. Nat Cell Biol 15(8):1001–1007. doi:10.1038/ncb2773 PubMedCrossRefGoogle Scholar
  84. 84.
    Murfuni I, Nicolai S, Baldari S, Crescenzi M, Bignami M, Franchitto A, Pichierri P (2013) The WRN and MUS81 proteins limit cell death and genome instability following oncogene activation. Oncogene 32(5):610–620. doi:10.1038/onc.2012.80 PubMedCrossRefGoogle Scholar
  85. 85.
    Schwartz M, Zlotorynski E, Goldberg M, Ozeri E, Rahat A, le Sage C, Chen BP, Chen DJ, Agami R, Kerem B (2005) Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability. Genes Dev 19(22):2715–2726PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Vernole P, Muzi A, Volpi A, Terrinoni A, Dorio AS, Tentori L, Shah GM, Graziani G (2011) Common fragile sites in colon cancer cell lines: role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1. Mutat Res 712(1–2):40–48. doi:10.1016/j.mrfmmm.2011.04.006 PubMedCrossRefGoogle Scholar
  87. 87.
    Pichierri P, Ammazzalorso F, Bignami M, Franchitto A (2011) The Werner syndrome protein: linking the replication checkpoint response to genome stability. Aging (Albany NY) 3(3):311–318 (100293 [pii])Google Scholar
  88. 88.
    Pichierri P, Nicolai S, Cignolo L, Bignami M, Franchitto A (2012) The RAD9-RAD1-HUS1 (9.1.1) complex interacts with WRN and is crucial to regulate its response to replication fork stalling. Oncogene 31(23):2809–2823. doi:10.1038/onc.2011.468 PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Sidorova JM, Li N, Folch A, Monnat RJ Jr (2008) The RecQ helicase WRN is required for normal replication fork progression after DNA damage or replication fork arrest. Cell Cycle 7(6):796–807PubMedCrossRefGoogle Scholar
  90. 90.
    Prince PR, Emond MJ, Monnat RJ Jr (2001) Loss of Werner syndrome protein function promotes aberrant mitotic recombination. Genes Dev 15(8):933–938. doi:10.1101/gad.877001 PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Sidorova JM, Kehrli K, Mao F, Monnat R Jr (2013) Distinct functions of human RECQ helicases WRN and BLM in replication fork recovery and progression after hydroxyurea-induced stalling. DNA Repair (Amst) 12(2):128–139. doi:10.1016/j.dnarep.2012.11.005 CrossRefGoogle Scholar
  92. 92.
    Kamath-Loeb AS, Loeb LA, Johansson E, Burgers PM, Fry M (2001) Interactions between the Werner syndrome helicase and DNA polymerase delta specifically facilitate copying of tetraplex and hairpin structures of the d(CGG)n trinucleotide repeat sequence. J Biol Chem 276(19):16439–16446. doi:10.1074/jbc.M100253200 PubMedCrossRefGoogle Scholar
  93. 93.
    Shah SN, Opresko PL, Meng X, Lee MY, Eckert KA (2010) DNA structure and the Werner protein modulate human DNA polymerase delta-dependent replication dynamics within the common fragile site FRA16D. Nucleic Acids Res 38(4):1149–1162. doi:10.1093/nar/gkp1131 PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    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. doi:10.1093/emboj/17.2.598 PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Takata M, Sasaki MS, Tachiiri S, Fukushima T, Sonoda E, Schild D, Thompson LH, Takeda S (2001) Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs. Mol Cell Biol 21(8):2858–2866. doi:10.1128/MCB.21.8.2858-2866.2001 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  1. 1.Section of Molecular Epidemiology, Department of Environment and Primary PreventionIstituto Superiore di SanitàRomeItaly
  2. 2.Section of Experimental and Computational Carcinogenesis, Department of Environment and Primary PreventionIstituto Superiore di SanitàRomeItaly
  3. 3.Genome Stability GroupIstituto Superiore di SanitàRomeItaly

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