1932

Abstract

Human cancers share properties referred to as hallmarks, among which sustained proliferation, escape from apoptosis, and genomic instability are the most pervasive. The sustained proliferation hallmark can be explained by mutations in oncogenes and tumor suppressors that regulate cell growth, whereas the escape from apoptosis hallmark can be explained by mutations in the , , or genes. A model to explain the presence of the three hallmarks listed above, as well as the patterns of genomic instability observed in human cancers, proposes that the genes driving cell proliferation induce DNA replication stress, which, in turn, generates genomic instability and selects for escape from apoptosis. Here, we review the data that support this model, as well as the mechanisms by which oncogenes induce replication stress. Further, we argue that DNA replication stress should be considered as a hallmark of cancer because it likely drives cancer development and is very prevalent.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathol-012414-040424
2015-01-24
2024-04-24
Loading full text...

Full text loading...

/deliver/fulltext/pathol/10/1/annurev-pathol-012414-040424.html?itemId=/content/journals/10.1146/annurev-pathol-012414-040424&mimeType=html&fmt=ahah

Literature Cited

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. 1.  2011. Global cancer statistics. CA: Cancer J. Clin. 61:269–90 [Google Scholar]
  2. Hanahan D, Weinberg RA. 2.  2000. The hallmarks of cancer. Cell 100:157–70 [Google Scholar]
  3. Hanahan D, Weinberg RA. 3.  2011. Hallmarks of cancer: the next generation. Cell 144:5646–74 [Google Scholar]
  4. Luo J, Solimini NL, Elledge SJ. 4.  2009. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136:5823–37 [Google Scholar]
  5. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. 5.  2013. Cancer genome landscapes. Science 339:61271546–58 [Google Scholar]
  6. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S. 6.  et al. 2013. Signatures of mutational processes in human cancer. Nature 500:7463415–21 [Google Scholar]
  7. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA. 7.  et al. 2014. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505:7484495–501 [Google Scholar]
  8. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B. 8.  et al. 2014. Mutational landscape and significance across 12 major cancer types. Nature 502:7471333–39 [Google Scholar]
  9. Bignell GR, Greenman CD, Davies H, Butler AP, Edkins S. 9.  et al. 2010. Signatures of mutation and selection in the cancer genome. Nature 463:7283893–98 [Google Scholar]
  10. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S. 10.  et al. 2010. The landscape of somatic copy-number alteration across human cancers. Nature 463:7283899–905 [Google Scholar]
  11. Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G. 11.  et al. 2013. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45:101134–40 [Google Scholar]
  12. Bishop JM. 12.  1987. The molecular genetics of cancer. Science 235:4786305–11 [Google Scholar]
  13. Land H, Parada LF, Weinberg RA. 13.  1983. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304:5927596–602 [Google Scholar]
  14. Weinberg RA. 14.  1995. The molecular basis of oncogenes and tumor suppressor genes. Ann. N. Y. Acad. Sci. 758:331–38 [Google Scholar]
  15. Ortega S, Malumbres M, Barbacid M. 15.  2002. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim. Biophys. Acta 1602:173–87 [Google Scholar]
  16. Serrano M, Gómez-Lahoz E, DePinho RA, Beach D, Bar-Sagi D. 16.  1995. Inhibition of ras-induced proliferation and cellular transformation by p16INK4. Science 267:5195249–52 [Google Scholar]
  17. Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA. 17.  1996. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85:127–37 [Google Scholar]
  18. Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J. 18.  et al. 1995. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 375:6531503–6 [Google Scholar]
  19. Dereli-Öz A, Versini G, Halazonetis TD. 19.  2011. Studies of genomic copy number changes in human cancers reveal signatures of DNA replication stress. Mol. Oncol. 5:4308–14 [Google Scholar]
  20. Le Beau MM, Drabkin H, Glover TW, Gemmill R, Rassool FV. 20.  et al. 1998. An FHIT tumor suppressor gene?. Genes Chromosomes Cancer 21:4281–89 [Google Scholar]
  21. Watanabe A, Hippo Y, Taniguchi H, Iwanari H, Yashiro M. 21.  et al. 2003. An opposing view on WWOX protein function as a tumor suppressor. Cancer Res. 63:248629–33 [Google Scholar]
  22. Aldaz CM, Ferguson BW, Abba MC. 22.  2014. WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies. Biochim. Biophys. Acta 1846:1188–200 [Google Scholar]
  23. Karras J, Paisie C, Huebner K. 23.  2014. Replicative stress and the FHIT gene: roles in tumor suppression, genome stability and prevention of carcinogenesis. Cancers 6:21208–19 [Google Scholar]
  24. Smith DI, Zhu Y, McAvoy S, Kuhn R. 24.  2006. Common fragile sites, extremely large genes, neural development and cancer. Cancer Lett. 232:148–57 [Google Scholar]
  25. Le Tallec B, Millot GA, Blin ME, Brison O, Dutrillaux B, Debatisse M. 25.  2013. Common fragile site profiling in epithelial and erythroid cells reveals that most recurrent cancer deletions lie in fragile sites hosting large genes. Cell Rep. 4:3420–28 [Google Scholar]
  26. Negrini S, Gorgoulis VG, Halazonetis TD. 26.  2010. Genomic instability—an evolving hallmark of cancer. Nat. Rev. Mol. Cell Biol. 11:3220–28 [Google Scholar]
  27. de Lange T. 27.  2005. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19:182100–10 [Google Scholar]
  28. Shay JW, Bacchetti S. 28.  1997. A survey of telomerase activity in human cancer. Eur. J. Cancer 33:5787–91 [Google Scholar]
  29. Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB. 29.  1992. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc. Natl. Acad. Sci. USA 89:167491–95 [Google Scholar]
  30. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW. 30.  1991. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51:23 Pt. 16304–11 [Google Scholar]
  31. Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y. 31.  et al. 1995. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268:52181749–53 [Google Scholar]
  32. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. 32.  1992. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:71237–45 [Google Scholar]
  33. Perciavalle RM, Stewart DP, Koss B, Lynch J, Milasta S. 33.  et al. 2012. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat. Cell Biol. 14:6575–83 [Google Scholar]
  34. Lengauer C, Kinzler KW, Vogelstein B. 34.  1997. Genetic instability in colorectal cancers. Nature 386:6625623–27 [Google Scholar]
  35. Lengauer C, Kinzler KW, Vogelstein B. 35.  1998. Genetic instabilities in human cancers. Nature 396:6712643–49 [Google Scholar]
  36. Bodmer W. 36.  2008. Genetic instability is not a requirement for tumor development. Cancer Res. 68:103558–61 [Google Scholar]
  37. Bunz F, Fauth C, Speicher MR, Dutriaux A, Sedivy JM. 37.  et al. 2002. Targeted inactivation of p53 in human cells does not result in aneuploidy. Cancer Res. 62:41129–33 [Google Scholar]
  38. Lane DP. 38.  1992. Cancer. p53, guardian of the genome. Nature 358:638115–16 [Google Scholar]
  39. Shiloh Y. 39.  2003. ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3:3155–68 [Google Scholar]
  40. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC. 40.  et al. 1999. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:6733271–75 [Google Scholar]
  41. van Haren J, Draegestein K, Keijzer N, Abrahams JP, Grosveld F. 41.  et al. 2009. Mammalian navigators are microtubule plus-end tracking proteins that can reorganize the cytoskeleton to induce neurite-like extensions. Cell Motil. Cytoskelet. 66:10824–38 [Google Scholar]
  42. Wilson BG, Roberts CWM. 42.  2011. SWI/SNF nucleosome remodellers and cancer. Nat. Rev. Cancer 11:7481–92 [Google Scholar]
  43. Fearon ER, Vogelstein B. 43.  1990. A genetic model for colorectal tumorigenesis. Cell 61:5759–67 [Google Scholar]
  44. Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR. 44.  et al. 1992. APC mutations occur early during colorectal tumorigenesis. Nature 359:6392235–37 [Google Scholar]
  45. Vogelstein B, Kinzler KW. 45.  1993. The multistep nature of cancer. Trends Genet. 9:4138–41 [Google Scholar]
  46. Jen J, Powell SM, Papadopoulos N, Smith KJ, Hamilton SR. 46.  et al. 1994. Molecular determinants of dysplasia in colorectal lesions. Cancer Res. 54:215523–26 [Google Scholar]
  47. Clevers H, Nusse R. 47.  2012. Wnt/β-catenin signaling and disease. Cell 149:61192–205 [Google Scholar]
  48. Nikolaev SI, Sotiriou SK, Pateras IS, Santoni F, Sougioultzis S. 48.  et al. 2012. A single-nucleotide substitution mutator phenotype revealed by exome sequencing of human colon adenomas. Cancer Res. 72:236279–89 [Google Scholar]
  49. Nordentoft I, Lamy P, Birkenkamp-Demtröder K, Shumansky K, Vang S. 49.  et al. 2014. Mutational context and diverse clonal development in early and late bladder cancer. Cell Rep. 7:51649–63 [Google Scholar]
  50. Hruban RH, Goggins M, Parsons J, Kern SE. 50.  2000. Progression model for pancreatic cancer. Clin. Cancer Res. 6:82969–72 [Google Scholar]
  51. Derry WB, Putzke AP, Rothman JH. 51.  2001. Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance. Science 294:5542591–95 [Google Scholar]
  52. Schumacher B, Hofmann K, Boulton S, Gartner A. 52.  2001. The C. elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis. Curr. Biol. 11:211722–27 [Google Scholar]
  53. Suh E-K, Yang A, Kettenbach A, Bamberger C, Michaelis AH. 53.  et al. 2006. P63 protects the female germ line during meiotic arrest. Nature 444:7119624–28 [Google Scholar]
  54. Levine AJ, Oren M. 54.  2009. The first 30 years of p53: growing ever more complex. Nat. Rev. Cancer 9:10749–58 [Google Scholar]
  55. Schultz LB, Chehab NH, Malikzay A, DiTullio RA, Stavridi ES, Halazonetis TD. 55.  2000. The DNA damage checkpoint and human cancer. Cold Spring Harb. Symp. Quant. Biol. 65:489–98 [Google Scholar]
  56. DiTullio RA, Mochan TA, Venere M, Bartkova J, Sehested M. 56.  et al. 2002. 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer. Nat. Cell Biol. 4:12998–1002 [Google Scholar]
  57. Bartkova J, Horejsí Z, Koed K, Krämer A, Tort F. 57.  et al. 2005. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434:7035864–70 [Google Scholar]
  58. Gorgoulis VG, Vassiliou L-VF, Karakaidos P, Zacharatos P, Kotsinas A. 58.  et al. 2005. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434:7035907–13 [Google Scholar]
  59. Evangelou K, Bartkova J, Kotsinas A, Pateras IS, Liontos M. 59.  et al. 2013. The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis. Cell Death Differ. 20:111485–97 [Google Scholar]
  60. Denko NC, Giaccia AJ, Stringer JR, Stambrook PJ. 60.  1994. The human Ha-ras oncogene induces genomic instability in murine fibroblasts within one cell cycle. Proc. Natl. Acad. Sci. USA 91:115124–28 [Google Scholar]
  61. Felsher DW, Bishop JM. 61.  1999. Transient excess of MYC activity can elicit genomic instability and tumorigenesis. Proc. Natl. Acad. Sci. USA 96:73940–44 [Google Scholar]
  62. Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P. 62.  et al. 2006. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444:7119638–42 [Google Scholar]
  63. Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D. 63.  et al. 2006. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444:7119633–37 [Google Scholar]
  64. Halazonetis TD. 64.  2004. Constitutively active DNA damage checkpoint pathways as the driving force for the high frequency of p53 mutations in human cancer. DNA Repair 3:8–91057–62 [Google Scholar]
  65. Sage J. 65.  2000. Targeted disruption of the three Rb-related genes leads to loss of G1 control and immortalization. Genes Dev. 14:233037–50 [Google Scholar]
  66. Reed KR, Meniel VS, Marsh V, Cole A, Sansom OJ, Clarke AR. 66.  2008. A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine. BMC Cancer 8:162 [Google Scholar]
  67. Méniel V, Megges M, Young MA, Cole A, Sansom OJ, Clarke AR. 67.  2014. Apc and p53 interaction in DNA damage and genomic instability in hepatocytes. Oncogene. doi:10.1038/onc.2014.342
  68. Osborn AJ, Elledge SJ, Zou L. 68.  2002. Checking on the fork: the DNA-replication stress-response pathway. Trends Cell Biol. 12:11509–16 [Google Scholar]
  69. Branzei D, Foiani M. 69.  2010. Maintaining genome stability at the replication fork. Nat. Rev. Mol. Cell Biol. 11:3208–19 [Google Scholar]
  70. Petermann E, Orta ML, Issaeva N, Schultz N, Helleday T. 70.  2010. Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Mol. Cell 37:4492–502 [Google Scholar]
  71. Cimprich KA, Cortez D. 71.  2008. ATR: an essential regulator of genome integrity. Nat. Rev. Mol. Cell Biol. 9:8616–27 [Google Scholar]
  72. Bensimon A, Simon A, Chiffaudel A, Croquette V, Heslot F, Bensimon D. 72.  1994. Alignment and sensitive detection of DNA by a moving interface. Science 265:51812096–98 [Google Scholar]
  73. Bester AC, Roniger M, Oren YS, Im MM, Sarni D. 73.  et al. 2011. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145:3435–46 [Google Scholar]
  74. Jones RM, Mortusewicz O, Afzal I, Lorvellec M, Garcia P. 74.  et al. 2013. Increased replication initiation and conflicts with transcription underlie cyclin E-induced replication stress. Oncogene 32:323744–53 [Google Scholar]
  75. Costantino L, Sotiriou SK, Rantala JK, Magin S, Mladenov E. 75.  et al. 2014. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science 343:616688–91 [Google Scholar]
  76. Srinivasan SV, Dominguez-Sola D, Wang LC, Hyrien O, Gautier J. 76.  2013. Cdc45 is a critical effector of Myc-dependent DNA replication stress. Cell Rep. 3:51629–39 [Google Scholar]
  77. Neelsen KJ, Zanini IMY, Herrador R, Lopes M. 77.  2013. Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates. J. Cell Biol. 200:6699–708 [Google Scholar]
  78. Glover TW, Berger C, Coyle J, Echo B. 78.  1984. DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum. Genet. 67:2136–42 [Google Scholar]
  79. Durkin SG, Glover TW. 79.  2007. Chromosome fragile sites. Annu. Rev. Genet. 41:1169–92 [Google Scholar]
  80. Arlt MF, Mulle JG, Schaibley VM, Ragland RL, Durkin SG. 80.  et al. 2009. Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants. Am. J. Hum. Genet. 84:3339–50 [Google Scholar]
  81. Arlt MF, Ozdemir AC, Birkeland SR, Wilson TE, Glover TW. 81.  2011. Hydroxyurea induces de novo copy number variants in human cells. Proc. Natl. Acad. Sci. USA 108:4217360–65 [Google Scholar]
  82. Tsantoulis PK, Kotsinas A, Sfikakis PP, Evangelou K, Sideridou M. 82.  et al. 2007. Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study. Oncogene 27:233256–64 [Google Scholar]
  83. Diffley JFX. 83.  2011. Quality control in the initiation of eukaryotic DNA replication. Philos. Trans. R. Soc. B: Biol. Sci. 366:15843545–53 [Google Scholar]
  84. Nishitani H, Lygerou Z. 84.  2002. Control of DNA replication licensing in a cell cycle. Genes Cells 7:6523–34 [Google Scholar]
  85. Diffley JF. 85.  2001. DNA replication: building the perfect switch. Curr. Biol. 11:9R367–70 [Google Scholar]
  86. Bell SP, Dutta A. 86.  2002. DNA replication in eukaryotic cells. Annu. Rev. Biochem. 71:333–74 [Google Scholar]
  87. Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M. 87.  1995. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol. Cell. Biol. 15:52612–24 [Google Scholar]
  88. Tanaka S, Diffley JFX. 88.  2002. Deregulated G1-cyclin expression induces genomic instability by preventing efficient pre-RC formation. Genes Dev. 16:202639–49 [Google Scholar]
  89. Lengronne A, Schwob E. 89.  2002. The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G(1). Mol. Cell 9:51067–78 [Google Scholar]
  90. Piatti S, Lengauer C, Nasmyth K. 90.  1995. Cdc6 is an unstable protein whose de novo synthesis in G1 is important for the onset of S phase and for preventing a “reductional” anaphase in the budding yeast Saccharomyces cerevisiae. EMBO J. 14:153788–99 [Google Scholar]
  91. Ekholm-Reed S, Méndez J, Tedesco D, Zetterberg A, Stillman B, Reed SI. 91.  2004. Deregulation of cyclin E in human cells interferes with prereplication complex assembly. J. Cell Biol. 165:6789–800 [Google Scholar]
  92. Frigola J, Remus D, Mehanna A, Diffley JFX. 92.  2014. ATPase-dependent quality control of DNA replication origin licensing. Nature 495:7441339–43 [Google Scholar]
  93. Mailand N, Diffley JFX. 93.  2005. CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. Cell 122:6915–26 [Google Scholar]
  94. Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R. 94.  et al. 2011. Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat. Struct. Mol. Biol. 18:121331–35 [Google Scholar]
  95. Beck H, Nahse-Kumpf V, Larsen MSY, O'Hanlon KA, Patzke S. 95.  et al. 2012. Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. Mol. Cell. Biol. 32:204226–36 [Google Scholar]
  96. Groth A, Corpet A, Cook AJL, Roche D, Bartek J. 96.  et al. 2007. Regulation of replication fork progression through histone supply and demand. Science 318:58581928–31 [Google Scholar]
  97. Mejlvang J, Feng Y, Alabert C, Neelsen KJ, Jasencakova Z. 97.  et al. 2014. New histone supply regulates replication fork speed and PCNA unloading. J. Cell Biol. 204:129–43 [Google Scholar]
  98. Toledo LI, Altmeyer M, Rask M-B, Lukas C, Larsen DH. 98.  et al. 2013. ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell 155:51088–103 [Google Scholar]
  99. Tanaka S, Nakato R, Katou Y, Shirahige K, Araki H. 99.  2011. Origin association of Sld3, Sld7, and Cdc45 proteins is a key step for determination of origin-firing timing. Curr. Biol. 21:242055–63 [Google Scholar]
  100. Mantiero D, Mackenzie A, Donaldson A, Zegerman P. 100.  2011. Limiting replication initiation factors execute the temporal programme of origin firing in budding yeast. EMBO J. 30:234805–14 [Google Scholar]
  101. Kafri R, Levy J, Ginzberg MB, Oh S, Lahav G, Kirschner MW. 101.  2013. Dynamics extracted from fixed cells reveal feedback linking cell growth to cell cycle. Nature 494:7438480–83 [Google Scholar]
  102. Barbet NC, Schneider U, Helliwell SB, Stansfield I, Tuite MF, Hall MN. 102.  1996. TOR controls translation initiation and early G1 progression in yeast. Mol. Biol. Cell 7:125–42 [Google Scholar]
  103. Resnitzky D, Gossen M, Bujard H, Reed SI. 103.  1994. Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. Mol. Cell. Biol. 14:31669–79 [Google Scholar]
  104. Dominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B. 104.  et al. 2007. Non-transcriptional control of DNA replication by c-Myc. Nature 448:7152445–51 [Google Scholar]
  105. Liu JJ, Chao JR, Jiang MC, Ng SY, Yen JJ, Yang-Yen HF. 105.  1995. Ras transformation results in an elevated level of cyclin D1 and acceleration of G1 progression in NIH 3T3 cells. Mol. Cell. Biol. 15:73654–63 [Google Scholar]
  106. Evertts AG, Coller HA. 106.  2012. Back to the origin: reconsidering replication, transcription, epigenetics, and cell cycle control. Genes Cancer 3:11–12678–96 [Google Scholar]
  107. Brewer BJ. 107.  1988. When polymerases collide: replication and the transcriptional organization of the E. coli chromosome. Cell 53:5679–86 [Google Scholar]
  108. Brewer BJ, Fangman WL. 108.  1988. A replication fork barrier at the 3′ end of yeast ribosomal RNA genes. Cell 55:4637–43 [Google Scholar]
  109. Necsulea A, Guillet C, Cadoret J-C, Prioleau M-N, Duret L. 109.  2009. The relationship between DNA replication and human genome organization. Mol. Biol. Evol. 26:4729–41 [Google Scholar]
  110. Knott SRV, Viggiani CJ, Aparicio OM. 110.  2009. To promote and protect: coordinating DNA replication and transcription for genome stability. Epigenetics 4:6362–65 [Google Scholar]
  111. Woodfine K, Fiegler H, Beare DM, Collins JE, McCann OT. 111.  et al. 2004. Replication timing of the human genome. Hum. Mol. Genet. 13:2191–202 [Google Scholar]
  112. Sasaki T, Ramanathan S, Okuno Y, Kumagai C, Shaikh SS, Gilbert DM. 112.  2006. The Chinese hamster dihydrofolate reductase replication origin decision point follows activation of transcription and suppresses initiation of replication within transcription units. Mol. Cell. Biol. 26:31051–62 [Google Scholar]
  113. Helmrich A, Ballarino M, Tora L. 113.  2011. Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol. Cell 44:6966–77 [Google Scholar]
  114. Barlow JH, Faryabi RB, Callén E, Wong N, Malhowski A. 114.  et al. 2013. Identification of early replicating fragile sites that contribute to genome instability. Cell 152:3620–32 [Google Scholar]
  115. Huertas P, Aguilera A. 115.  2003. Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol. Cell 12:3711–21 [Google Scholar]
  116. Tuduri S, Crabbé L, Conti C, Tourrière H, Holtgreve-Grez H. 116.  et al. 2009. Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription. Nat. Cell Biol. 11:111315–24 [Google Scholar]
  117. Durkin SG, Ragland RL, Arlt MF, Mulle JG, Warren ST, Glover TW. 117.  2008. Replication stress induces tumor-like microdeletions in FHIT/FRA3B. Proc. Natl. Acad. Sci. USA 105:1246–51 [Google Scholar]
  118. Pasi CE, Dereli-Öz A, Negrini S, Friedli M, Fragola G. 118.  et al. 2011. Genomic instability in induced stem cells. Cell Death Differ. 18:5745–53 [Google Scholar]
  119. Letessier A, Millot GA, Koundrioukoff S, Lachagès A-M, Vogt N. 119.  et al. 2011. Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature 470:7332120–23 [Google Scholar]
  120. Burrow AA, Marullo A, Holder LR, Wang YH. 120.  2010. Secondary structure formation and DNA instability at fragile site FRA16B. Nucleic Acids Res. 38:92865–77 [Google Scholar]
  121. Ozeri-Galai E, Lebofsky R, Rahat A, Bester AC, Bensimon A, Kerem B. 121.  2011. Failure of origin activation in response to fork stalling leads to chromosomal instability at fragile sites. Mol. Cell 43:1122–31 [Google Scholar]
  122. Le Beau MM, Rassool FV, Neilly ME, Espinosa R, Glover TW. 122.  et al. 1998. Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction. Hum. Mol. Genet. 7:4755–61 [Google Scholar]
  123. Chan KL, Palmai-Pallag T, Ying S, Hickson ID. 123.  2009. Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat. Cell Biol. 11:6753–60 [Google Scholar]
  124. Burrell RA, McClelland SE, Endesfelder D, Groth P, Weller M-C. 124.  et al. 2013. Replication stress links structural and numerical cancer chromosomal instability. Nature 494:7438492–96 [Google Scholar]
  125. Lukas C, Savic V, Bekker-Jensen S, Doil C, Neumann B. 125.  et al. 2011. 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress. Nat. Cell Biol. 13:3243–53 [Google Scholar]
  126. Arlt MF, Rajendran S, Birkeland SR, Wilson TE, Glover TW. 126.  2013. Copy number variants are produced in response to low-dose ionizing radiation in cultured cells. Environ. Mol. Mutagen. 55:2103–13 [Google Scholar]
  127. Llorente B, Smith CE, Symington LS. 127.  2008. Break-induced replication: What is it and what is it for?. Cell Cycle 7:7859–64 [Google Scholar]
  128. Anand RP, Lovett ST, Haber JE. 128.  2013. Break-induced DNA replication. Cold Spring Harb. Perspect. Biol. 5:12a010397 [Google Scholar]
  129. Payen C, Koszul R, Dujon B, Fischer G. 129.  2008. Segmental duplications arise from Pol32-dependent repair of broken forks through two alternative replication-based mechanisms. PLOS Genet. 4:9e1000175 [Google Scholar]
  130. Saini N, Ramakrishnan S, Elango R, Ayyar S, Zhang Y. 130.  et al. 2014. Migrating bubble during break-induced replication drives conservative DNA synthesis. Nature 502:7471389–92 [Google Scholar]
  131. Deem A, Keszthelyi A, Blackgrove T, Vayl A, Coffey B. 131.  et al. 2011. Break-induced replication is highly inaccurate. PLOS Biol. 9:2e1000594 [Google Scholar]
  132. Jackson AL, Loeb LA. 132.  2001. The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutat. Res. 477:1–27–21 [Google Scholar]
  133. Ziech D, Franco R, Pappa A, Panayiotidis MI. 133.  2011. Reactive oxygen species (ROS)–induced genetic and epigenetic alterations in human carcinogenesis. Mutat. Res. 711:1–2167–73 [Google Scholar]
  134. de Lange T. 134.  2005. Telomere-related genome instability in cancer. Cold Spring Harb. Symp. Quant. Biol. 70:0197–204 [Google Scholar]
  135. O'Hagan RC, Chang S, Maser RS, Mohan R, Artandi SE. 135.  et al. 2002. Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2:2149–55 [Google Scholar]
  136. Gisselsson D, Pettersson L, Höglund M, Heidenblad M, Gorunova L. 136.  et al. 2000. Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc. Natl. Acad. Sci. USA 97:105357–62 [Google Scholar]
  137. Ganem NJ, Pellman D. 137.  2012. Linking abnormal mitosis to the acquisition of DNA damage. J. Cell Biol. 199:6871–81 [Google Scholar]
  138. Janssen A, van der Burg M, Szuhai K, Kops GJPL, Medema RH. 138.  2011. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 333:60511895–98 [Google Scholar]
  139. McClintock B. 139.  1938. The production of homozygous deficient tissues with mutant characteristics by means of the aberrant mitotic behavior of ring-shaped chromosomes. Genetics 23:4315–76 [Google Scholar]
  140. McClintock B. 140.  1941. The stability of broken ends of chromosomes in Zea mays. Genetics 26:2234–82 [Google Scholar]
  141. McBride DJ, Etemadmoghadam D, Cooke SL, Alsop K, George J. 141.  et al. 2012. Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes. J. Pathol. 227:4446–55 [Google Scholar]
  142. Stephens PJ, McBride DJ, Lin M-L, Varela I, Pleasance ED. 142.  et al. 2009. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462:72761005–10 [Google Scholar]
  143. Cooper DN, Youssoufian H. 143.  1988. The CpG dinucleotide and human genetic disease. Hum. Genet. 78:2151–55 [Google Scholar]
  144. Woo YH, Li W-H. 144.  2012. DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes. Nat. Comms. 3:1004 [Google Scholar]
  145. Liu L, De S, Michor F. 145.  2013. DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes. Nat. Commun. 4:1502 [Google Scholar]
  146. Schuster-Böckler B, Lehner B. 146.  2012. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature 488:7412504–7 [Google Scholar]
  147. Schepeler T, Lamy P, Hvidberg V, Laurberg JR, Fristrup N. 147.  et al. 2013. A high resolution genomic portrait of bladder cancer: correlation between genomic aberrations and the DNA damage response. Oncogene 32:313577–86 [Google Scholar]
  148. Artandi SE, DePinho RA. 148.  2010. Telomeres and telomerase in cancer. Carcinogenesis 31:19–18 [Google Scholar]
  149. Halazonetis TD, Gorgoulis VG, Bartek J. 149.  2008. An oncogene-induced DNA damage model for cancer development. Science 319:58681352–55 [Google Scholar]
  150. Michaloglou C, Vredeveld LCW, Soengas MS, Denoyelle C, Kuilman T. 150.  et al. 2005. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436:7051720–24 [Google Scholar]
/content/journals/10.1146/annurev-pathol-012414-040424
Loading
/content/journals/10.1146/annurev-pathol-012414-040424
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error