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Chromothripsis pp 231-251 | Cite as

Genes, Proteins, and Biological Pathways Preventing Chromothripsis

  • Martin Poot
Protocol
First Online:
Part of the Methods in Molecular Biology book series (MIMB, volume 1769)

Abstract

The highly complex structural genome variations chromothripsis, chromoanasynthesis, and chromoplexy are subsumed under the term chromoanagenesis, which means chromosome rebirth. Precipitated by numerous DNA double-strand breaks, they differ in number of and distances between breakpoints, associated copy number variations, order and orientation of segments, and flanking sequences at joining points. Results from patients with the autosomal dominant cancer susceptibility disorder Li-Fraumeni syndrome implicated somatic TP53 mutations in chromothripsis. TP53 participates in the G2/M phase checkpoint, halting cell cycling after premature chromosome compaction during the second half of the S phase, thus preventing chromosome shattering. By experimental TP53 ablation and micronucleus induction, one or a few isolated chromosomes underwent desynchronized replication and chromothripsis. Secondly, chromothripsis occurred after experimental induction of telomere crisis after which dicentric chromosomes sustained TREX1-mediated resolution of chromosome bridges and kataegis. Third, DNA polymerase Polθ-dependent chromothripsis has been documented. Finally, a family with chromothripsis after L1 element-dependent retrotransposition and Alu/Alu homologous recombination has been reported. Human chromosomal instability syndromes share defects in responses to DNA double-strand breaks, characteristic cell cycle perturbations, elevated rates of micronucleus formation, premature chromosome compaction, and apoptosis. They are also associated with elevated susceptibility to malignant disease, such as medulloblastomas and gliomas in ataxia-telangiectasia, leukemia and lymphoma in Bloom syndrome, and osteosarcoma and soft tissue sarcoma in Werner syndrome. The latter syndrome is characterized by a premature aging-like progressive decline of mesenchymal tissues. In all thus far studied cases, constitutional chromothripsis occurred in the male germline and male patients with defects in the double-strand break response genes ATM, MRE11, BLM, LIG4, WRN, and Ku70 show impaired fertility. Conceivably, chromothripsis may, in a stochastic rather than deterministic way, be implicated in germline structural variation, malignant disease, premature aging, genome mosaicism in somatic tissues, and male infertility.

Key words

Chromoanagenesis Chromoanasynthesis Chromoplexy Nonhomologous end joining (NHEJ) Microhomology-mediated break-induced repair (MMBIR) TP53 WRN helicase exonuclease 
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References

  1. 1.
    Boveri T (1914) Zur Frage der Entstehung maligner Tumoren. Fischer, JenaGoogle Scholar
  2. 2.
    Poot M, Haaf T (2015) Mechanisms of origin, phenotypic effects and diagnostic implications of complex chromosome rearrangements. Mol Syndromol 6:110–134CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Pellestor F, Anahory T, Lefort G et al (2011) Complex chromosomal rearrangements: origin and meiotic behavior. Hum Reprod Update 17:476–494CrossRefPubMedGoogle Scholar
  4. 4.
    Liu P, Carvalho CM, Hastings PJ et al (2012) Mechanisms for recurrent and complex human genomic rearrangements. Curr Opin Genet Dev 22:211–220CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Liu G, Stevens JB, Horne SD et al (2014) Genome chaos: survival strategy during crisis. Cell Cycle 13:528–537CrossRefPubMedGoogle Scholar
  6. 6.
    Liu P, Erez A, Nagamani SC et al (2011) Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146:889–903CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Stephens PJ, Greenman CD, Fu B et al (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:27–40CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Rausch T, Jones DT, Zapatka M et al (2012) Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148:59–71CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Holland AJ, Cleveland DW (2012) Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nat Med 18:1630–1638CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zhang CZ, Leibowitz ML, Pellman D (2013) Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes Dev 27:2513–2530CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Pellestor F, Gatinois V, Puechberty J et al (2014) Chromothripsis: potential origin in gametogenesis and preimplantation cell divisions. A review. Fertil Steril 102:1785–1796CrossRefPubMedGoogle Scholar
  12. 12.
    Nazaryan-Petersen L, Tommerup N (2016) Chromothripsis and human genetic disease. eLS:1–10.  https://doi.org/10.1002/9780470015902.a0024627
  13. 13.
    Fukami M, Shima H, Suzuki E et al (2017) Catastrophic cellular events leading to complex chromosomal rearrangements in the germline. Clin Genet 91:653–660CrossRefPubMedGoogle Scholar
  14. 14.
    Baca SC, Prandi D, Lawrence MS et al (2013) Punctuated evolution of prostate cancer genomes. Cell 153:666–677CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Korbel JO, Campbell PJ (2013) Criteria for inference of chromothripsis in cancer genomes. Cell 152:1226–1236CrossRefPubMedGoogle Scholar
  16. 16.
    Kloosterman WP, Guryev V, van Roosmalen M et al (2011) Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline. Hum Mol Genet 20:1916–1924CrossRefPubMedGoogle Scholar
  17. 17.
    Kloosterman WP, Tavakoli-Yaraki M, van Roosmalen MJ (2012) Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms. Cell Rep 1:648–655CrossRefPubMedGoogle Scholar
  18. 18.
    Ratnaparkhe M, Hlevnjak M, Kolb T et al (2017) Genomic profiling of acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis. Leukemia 31(10):2048–2056.  https://doi.org/10.1038/leu.2017.55 CrossRefPubMedGoogle Scholar
  19. 19.
    Masset H, Hestand MS, Van Esch H et al (2016) A distinct class of chromoanagenesis events characterized by focal copy number gains. Hum Mutat 37:661–668CrossRefPubMedGoogle Scholar
  20. 20.
    Nazaryan-Petersen L, Bertelsen B, Bak M et al (2016) Germline chromothripsis driven by L1-mediated retrotransposition and Alu/Alu homologous recombination. Hum Mutat 37:385–395CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang CZ, Spektor A, Cornils H et al (2015) Chromothripsis from DNA damage in micronuclei. Nature 522:179–184CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Maciejowski J, Li Y, Bosco N et al (2015) Chromothripsis and kataegis induced by telomere crisis. Cell 163:1641–1654CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Yang J, Liu J, Ouyang L et al (2016) CTLPScanner: a web server for chromothripsis-like pattern detection. Nucleic Acids Res 44:W252–W258CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Nazaryan L, Stefanou EG, Hansen C et al (2014) The strength of combined cytogenetic and mate-pair sequencing techniques illustrated by a germline chromothripsis rearrangement involving FOXP2. Eur J Hum Genet 22:338–343CrossRefPubMedGoogle Scholar
  25. 25.
    Weckselblatt B, Rudd MK (2015) Human structural variation: mechanisms of chromosome rearrangements. Trends Genet 31:587–599CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Weckselblatt B, Hermetz KE, Rudd MK (2015) Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis. Genome Res 25:937–947CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Marcozzi A, Pellestor F, Kloosterman WP (2017) The genomic characteristics and origin of chromothripsis. In: Pellestor F (ed) Chromothripsis. Springer, New YorkGoogle Scholar
  28. 28.
    Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432:316–323CrossRefPubMedGoogle Scholar
  29. 29.
    Meyerson M, Pellman D (2011) Cancer genomes evolve by pulverizing single chromosomes. Cell 144:9–10CrossRefPubMedGoogle Scholar
  30. 30.
    Crasta K, Ganem NJ, Dagher R et al (2012) DNA breaks and chromosome pulverization from errors in mitosis. Nature 482:53–58CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Poot M, Hoehn H, Rünger TM et al (1992) Impaired S-phase transit of Werner syndrome cells expressed in lymphoblastoid cell lines. Exp Cell Res 202:267–273CrossRefPubMedGoogle Scholar
  32. 32.
    Poot M, Gollahon KA, Rabinovitch PS (1999) Werner syndrome lymphoblastoid cells are sensitive to camptothecin-induced apoptosis in S phase. Hum Genet 104:10–14CrossRefPubMedGoogle Scholar
  33. 33.
    Honma M, Tadokoro S, Sakamoto H et al (2002) Chromosomal instability in B-lymphoblasotoid cell lines from Werner and Bloom syndrome patients. Mutat Res 520:15–24CrossRefPubMedGoogle Scholar
  34. 34.
    Trkova M, Prochazkova K, Krutilkova V et al (2007) Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. Cancer 110:694–702CrossRefPubMedGoogle Scholar
  35. 35.
    Tusell L, Pampalona J, Soler D et al (2010) Different outcomes of telomere-dependent anaphase bridges. Biochem Soc Trans 38:1698–1703CrossRefPubMedGoogle Scholar
  36. 36.
    Thanasoula M, Escandell JM, Martinez P et al (2010) p53 prevents entry into mitosis with uncapped telomeres. Curr Biol 20:521–526CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Haaf T, Raderschall E, Reddy G et al (1999) Sequestration of mammalian Rad51-recombination protein into micronuclei. J Cell Biol 144:11–20CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Darzynkiewicz Z, Li X, Bedner E (2001) Use of flow and laser-scanning cytometry in analysis of cell death. Methods Cell Biol 66:69–109CrossRefPubMedGoogle Scholar
  39. 39.
    Sakofsky CJ, Ayyar S, Deem AK et al (2015) Translesion polymerases drive microhomology-mediated break-induced replication leading to complex chromosomal rearrangements. Mol Cell 60:860–872CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Ahmed EA, Sfeir A, Takai H et al (2013) Ku70 and non-homologous end joining protect testicular cells from DNA damage. J Cell Sci 126:3095–3104CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Den Boer PJ, Poot M, Verkerk A et al (1990) Glutathione-dependent defence mechanisms in isolated round spermatids from the rat. Int J Androl 13:26–38CrossRefGoogle Scholar
  42. 42.
    Maciejowski J, de Lange T (2017) Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol 18(3):175–186CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Roberts SA, Sterling J, Thompson C et al (2012) Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol Cell 46:424–435CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Roberts SA, Gordenin DA (2014) Hypermutation in human cancer genomes: footprints and mechanisms. Nat Rev Cancer 14:786–800CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Cai H, Kumar N, Bagheri HC et al (2014) Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens. BMC Genomics 15:82.  https://doi.org/10.1186/1471-2164-15-82 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Rode A, Maass KK, Willmund KV et al (2016) Chromothripsis in cancer cells: an update. Int J Cancer 138:2322–2333CrossRefPubMedGoogle Scholar
  47. 47.
    Beck CR, Collier P, Macfarlane C et al (2010) LINE-1 retrotransposition activity in human genomes. Cell 141:1159–1170CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Startek M, Szafranski P, Gambin T et al (2015) Genome-wide analyses of LINE-LINE-mediated nonallelic homologous recombination. Nucleic Acids Res 43:2188–2198CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Bertelsen B, Nazaryan-Petersen L, Sun W et al (2016) A germline chromothripsis event stably segregating in 11 individuals through three generations. Genet Med 18:494–500CrossRefPubMedGoogle Scholar
  50. 50.
    Lieber MR (2010) The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 79:181–211CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Georgiou I, Noutsopoulos D, Dimitriadou E et al (2009) Retrotransposon RNA expression and evidence for retrotransposition events in human oocytes. Hum Mol Genet 18:1221–1228CrossRefPubMedGoogle Scholar
  52. 52.
    McConnell MJ, Lindberg MR, Brennand KJ et al (2013) Mosaic copy number variation in human neurons. Science 342:632–637CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Erwin JA, Paquola AC, Singer T et al (2016) L1-associated genomic regions are deleted in somatic cells of the healthy human brain. Nat Neurosci 19:1583–1591CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Rulten SL, Grundy GJ (2017) Non-homologous end joining: common interaction sites and exchange of multiple factors in the DNA repair process. Bioessays 39.  https://doi.org/10.1002/bies.201600209
  55. 55.
    Hustedt N, Durocher D (2016) The control of DNA repair by the cell cycle. Nat Cell Biol 19:1–9CrossRefPubMedGoogle Scholar
  56. 56.
    Pierce AJ, Jasin M (2001) NHEJ deficiency and disease. Mol Cell 8:1160–1161CrossRefPubMedGoogle Scholar
  57. 57.
    Patro BS, Frøhlich R, Bohr VA et al (2011) WRN helicase regulates the ATR-CHK1-induced S-phase checkpoint pathway in response to topoisomerase-I-DNA covalent complexes. J Cell Sci 124:3967–3979CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Su F, Mukherjee S, Yang Y et al (2014) Nonenzymatic role for WRN in preserving nascent DNA strands after replication stress. Cell Rep 9:1387–1401CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Shamanna RA, Lu H, de Freitas JK et al (2016) WRN regulates pathway choice between classical and alternative non-homologous end joining. Nat Commun 7:13785.  https://doi.org/10.1038/ncomms13785 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Rünger TM, Bauer C, Dekant B et al (1994) Hypermutable ligation of plasmid DNA ends in cells from patients with Werner syndrome. J Invest Dermatol 102:45–48CrossRefPubMedGoogle Scholar
  61. 61.
    Palermo V, Rinalducci S, Sanchez M et al (2016) CDK1 phosphorylates WRN at collapsed replication forks. Nat Commun 7:12880.  https://doi.org/10.1038/ncomms12880 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Wu L, Hickson ID (2001) Molecular biology. DNA ends ReQ-uire attention. Science 292:229–230CrossRefPubMedGoogle Scholar
  63. 63.
    Cejka P, Cannavo E, Polaczek P et al (2010) DNA end resection by Dna2-Sgs1-RPA and its stimulation by Top3-Rmi1 and Mre11-Rad50-Xrs2. Nature 467:112–116CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Grabarz A, Guirouilh-Barbat J, Barascu A et al (2013) A role for BLM in double-strand break repair pathway choice: prevention of CtIP/Mre11-mediated alternative nonhomologous end-joining. Cell Rep 5:21–28CrossRefPubMedGoogle Scholar
  65. 65.
    Sturzenegger A, Burdova K, Kanagaraj R et al (2014) DNA2 cooperates with the WRN and BLM RecQ helicases to mediate long-range DNA end resection in human cells. J Biol Chem 289:27314–27326CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Goto M, Miller RW, Ishikawa Y et al (1996) Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomark Prev 5:239–246Google Scholar
  67. 67.
    Poot M, Yom JS, Whang SH et al (2001) Werner syndrome cells are sensitive to DNA cross-linking drugs. FASEB J 15:1224–1226CrossRefPubMedGoogle Scholar
  68. 68.
    Poot M, Gollahon KA, Emond MJ et al (2002) Werner syndrome diploid fibroblasts are sensitive to 4-nitroquinoline-N-oxide and 8-methoxypsoralen: implications for the disease phenotype. FASEB J 16:757–758CrossRefPubMedGoogle Scholar
  69. 69.
    Poot M, Jin X, Hill JP et al (2004) Distinct functions for WRN and TP53 in a shared pathway of cellular response to 1-beta-D-arabinofuranosylcytosine and bleomycin. Exp Cell Res 296:327–336CrossRefPubMedGoogle Scholar
  70. 70.
    Epstein CJ, Martin GM, Schultz AL et al (1966) Werner’s syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore) 45:177–221CrossRefGoogle Scholar
  71. 71.
    Rünger TM, Poot M, Kraemer KH (1992) Abnormal processing of transfected plasmid DNA in cells from patients with ataxia telangiectasia. Mutat Res 293:47–54CrossRefPubMedGoogle Scholar
  72. 72.
    O’Driscoll M, Jeggo PA (2006) The role of double-strand break repair -insights from human genetics. Nat Rev Genet 7:45–54CrossRefPubMedGoogle Scholar
  73. 73.
    Scott SP, Pandita TK (2006) The cellular control of DNA double-strand breaks. J Cell Biochem 99:1463–1475CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Salk D, Au K, Hoehn H, Martin GM (1981) Cytogenetics of Werner’s syndrome cultured skin fibroblasts: variegated translocation mosaicism. Cytogenet Cell Genet 30:92–107CrossRefPubMedGoogle Scholar
  75. 75.
    Fukuchi K, Martin GM, Monnat RJ Jr (1989) Mutator phenotype of Werner syndrome is characterized by extensive deletions. Proc Natl Acad Sci U S A 86:5893–5897CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Ogburn CE, Oshima J, Poot M et al (1997) An apoptosis-inducing genotoxin differentiates heterozygotic carriers for Werner helicase mutations from wild-type and homozygous mutants. Hum Genet 101:121–125CrossRefPubMedGoogle Scholar
  77. 77.
    Kamath-Loeb AS, Loeb LA, Johansson E et al (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 276:16439–16446CrossRefPubMedGoogle Scholar
  78. 78.
    Dhillon KK, Sidorova J, Saintigny Y et al (2007) Functional role of the Werner syndrome RecQ helicase in human fibroblasts. Aging Cell 6:53–61CrossRefPubMedGoogle Scholar
  79. 79.
    Rosin MP, German J (1985) Evidence for chromosome instability in vivo in Bloom syndrome: increased numbers of micronuclei in exfoliated cells. Hum Genet 71:187–191CrossRefPubMedGoogle Scholar
  80. 80.
    Li GC, Ouyang H, Li X (1998) Ku70: a candidate tumor suppressor gene for murine T cell lymphoma. Mol Cell 2:1–8CrossRefPubMedGoogle Scholar
  81. 81.
    Suzuki T, Yasui M, Honma M (2016) Mutator phenotype and DNA double-strand break repair in BLM helicase-deficient human cells. Mol Cell Biol 36:2877–2889CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Imamura O, Fujita K, Shimamoto A et al (2001) Bloom helicase is involved in DNA surveillance in early S phase in vertebrate cells. Oncogene 20:1143–1151CrossRefPubMedGoogle Scholar
  83. 83.
    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 17:410–416CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Baillie JK, Barnett MW, Upton KR et al (2011) Somatic retrotransposition alters the genetic landscape of the human brain. Nature 479:534–537CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Martin Poot
    • 1
  1. 1.Department of Human GeneticsUniversity of WürzburgWürzburgGermany

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