1932

Abstract

In a lifetime, a human being synthesizes approximately 2×1016 meters of DNA, a distance that corresponds to 130,000 times the distance between the Earth and the Sun. This daunting task is executed by thousands of replication forks, which progress along the chromosomes and frequently stall when they encounter DNA lesions, unusual DNA structures, RNA polymerases, or tightly-bound protein complexes. To complete DNA synthesis before the onset of mitosis, eukaryotic cells have evolved complex mechanisms to process and restart arrested forks through the coordinated action of multiple nucleases, topoisomerases, and helicases. In this review, we discuss recent advances in understanding the role and regulation of nucleases acting at stalled forks with a focus on the nucleolytic degradation of nascent DNA, a process commonly referred to as fork resection. We also discuss the effects of deregulated fork resection on genomic instability and on the unscheduled activation of the interferon response under replication stress conditions.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genet-120116-024745
2017-11-27
2024-12-13
Loading full text...

Full text loading...

/deliver/fulltext/genet/51/1/annurev-genet-120116-024745.html?itemId=/content/journals/10.1146/annurev-genet-120116-024745&mimeType=html&fmt=ahah

Literature Cited

  1. Abbas T, Keaton MA, Dutta A. 1.  2013. Genomic instability in cancer. Cold Spring Harb. Perspect. Biol. 5:a012914 [Google Scholar]
  2. Abe T, Harashima A, Xia T, Konno H, Konno K. 2.  et al. 2013. STING recognition of cytoplasmic DNA instigates cellular defense. Mol. Cell 50:5–15 [Google Scholar]
  3. Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V. 3.  2014. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J. Immunol. 192:5993–97 [Google Scholar]
  4. Aguilera A, García-Muse T. 4.  2013. Causes of genome instability. Annu. Rev. Genet. 47:1–32 [Google Scholar]
  5. Ahn JS, Osman F, Whitby MC. 5.  2005. Replication fork blockage by RTS1 at an ectopic site promotes recombination in fission yeast. EMBO J 24:2011–23 [Google Scholar]
  6. Ait Saada A, Teixeira-Silva A, Iraqui I, Costes A, Hardy J. 6.  et al. 2017. Unprotected replication forks are converted into mitotic sister chromatid bridges. Mol. Cell 66:398–410.e4 [Google Scholar]
  7. Alabert C, Bianco JN, Pasero P. 7.  2009. Differential regulation of homologous recombination at DNA breaks and replication forks by the Mrc1 branch of the S-phase checkpoint. EMBO J 28:1131–41 [Google Scholar]
  8. Anand R, Ranjha L, Cannavo E, Cejka P. 8.  2016. Phosphorylated CtIP functions as a co-factor of the MRE11-RAD50-NBS1 endonuclease in DNA end resection. Mol. Cell 64:940–50 [Google Scholar]
  9. Anand RP, Lovett ST, Haber JE. 9.  2013. Break-induced DNA replication. Cold Spring Harb. Perspect. Biol. 5:a010397 [Google Scholar]
  10. Atkinson J, McGlynn P. 10.  2009. Replication fork reversal and the maintenance of genome stability. Nucleic Acids Res 37:3475–92 [Google Scholar]
  11. Bae S-H, Bae K-H, Kim J-A, Seo Y-S. 11.  2001. RPA governs endonuclease switching during processing of Okazaki fragments in eukaryotes. Nature 412:456–61 [Google Scholar]
  12. Balakrishnan L, Bambara RA. 12.  2013. Flap endonuclease 1. Annu. Rev. Biochem. 82:119–38 [Google Scholar]
  13. Ballana E, Este JA. 13.  2015. SAMHD1: at the crossroads of cell proliferation, immune responses, and virus restriction. Trends Microbiol 23:680–92 [Google Scholar]
  14. Barber GN. 14.  2015. STING: infection, inflammation and cancer. Nat. Rev. Immunol. 15:760–70 [Google Scholar]
  15. Barlow JH, Rothstein R. 15.  2009. Rad52 recruitment is DNA replication independent and regulated by Cdc28 and the Mec1 kinase. EMBO J 28:1121–30 [Google Scholar]
  16. Bass TE, Luzwick JW, Kavanaugh G, Carroll C, Dungrawala H. 16.  et al. 2016. ETAA1 acts at stalled replication forks to maintain genome integrity. Nat. Cell Biol. 18:1185–95 [Google Scholar]
  17. Beloglazova N, Flick R, Tchigvintsev A, Brown G, Popovic A. 17.  et al. 2013. Nuclease activity of the human SAMHD1 protein implicated in the Aicardi-Goutières Syndrome and HIV-1 restriction. J. Biol. Chem. 288:8101–10 [Google Scholar]
  18. Berti M, Ray Chaudhuri A, Thangavel S, Gomathinayagam S, Kenig S. 18.  et al. 2013. Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat. Struct. Mol. Biol. 20:347–54 [Google Scholar]
  19. Berti M, Vindigni A. 19.  2016. Replication stress: getting back on track. Nat. Struct. Mol. Biol. 23:103–9 [Google Scholar]
  20. Betous R, Couch FB, Mason AC, Eichman BF, Manosas M, Cortez D. 20.  2013. Substrate-selective repair and restart of replication forks by DNA translocases. Cell Rep 3:1958–69 [Google Scholar]
  21. Bianchi J, Rudd SG, Jozwiakowski SK, Bailey LJ, Soura V. 21.  et al. 2013. PrimPol bypasses UV photoproducts during eukaryotic chromosomal DNA replication. Mol. Cell 52:566–73 [Google Scholar]
  22. Bizard AH, Hickson ID. 22.  2014. The dissolution of double Holliday junctions. Cold Spring Harb. Perspect. Biol. 6:a016477 [Google Scholar]
  23. Blastyák A, Hajdú I, Unk I, Haracska L. 23.  2010. Role of double-stranded DNA translocase activity of human HLTF in replication of damaged DNA. Mol. Cell. Biol. 30:684–93 [Google Scholar]
  24. Blastyák A, Pintér L, Unk I, Prakash L, Prakash S, Haracska L. 24.  2007. Yeast Rad5 protein required for postreplication repair has a DNA helicase activity specific for replication fork regression. Mol. Cell 28:167–75 [Google Scholar]
  25. Bleichert F, Botchan MR, Berger JM. 25.  2017. Mechanisms for initiating cellular DNA replication. Science 355:eaah6317 [Google Scholar]
  26. Boddy MN, Lopez-Girona A, Shanahan P, Interthal H, Heyer WD, Russell P. 26.  2000. Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1. Mol. Cell. Biol. 20:8758–66 [Google Scholar]
  27. Branzei D, Psakhye I. 27.  2016. DNA damage tolerance. Curr. Opin. Cell Biol. 40:137–44 [Google Scholar]
  28. Bugreev DV, Rossi MJ, Mazin AV. 28.  2011. Cooperation of RAD51 and RAD54 in regression of a model replication fork. Nucleic Acids Res 39:2153–64 [Google Scholar]
  29. Byun TS, Pacek M, Yee MC, Walter JC, Cimprich KA. 29.  2005. Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev 19:1040–52 [Google Scholar]
  30. Cannavo E, Cejka P, Kowalczykowski SC. 30.  2013. Relationship of DNA degradation by Saccharomyces cerevisiae Exonuclease 1 and its stimulation by RPA and Mre11-Rad50-Xrs2 to DNA end resection. PNAS 110:E1661–68 [Google Scholar]
  31. Cejka P, Cannavo E, Polaczek P, Masuda-Sasa T, Pokharel S. 31.  et al. 2010. DNA end resection by Dna2-Sgs1-RPA and its stimulation by Top3-Rmi1 and Mre11-Rad50-Xrs2. Nature 467:112–16 [Google Scholar]
  32. Chanut P, Britton S, Coates J, Jackson SP, Calsou P. 32.  2016. Coordinated nuclease activities counteract Ku at single-ended DNA double-strand breaks. Nat. Commun. 7:12889 [Google Scholar]
  33. Chaudhury I, Stroik DR, Sobeck A. 33.  2014. FANCD2-controlled chromatin access of the Fanconi-associated nuclease FAN1 is crucial for the recovery of stalled replication forks. Mol. Cell. Biol. 34:3939–54 [Google Scholar]
  34. Cheng IC, Chen BC, Shuai HH, Chien FC, Chen P, Hsieh TS. 34.  2016. Wuho is a new member in maintaining genome stability through its interaction with flap endonuclease 1. PLOS Biol 14:e1002349 [Google Scholar]
  35. Ciccia A, Nimonkar Amitabh V, Hu Y, Hajdu I, Achar Yathish J. 35.  et al. 2012. Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress. Mol. Cell 47:396–409 [Google Scholar]
  36. Cimprich KA, Cortez D. 36.  2008. ATR: an essential regulator of genome integrity. Nat. Rev. Mol. Cell Biol. 9:616–27 [Google Scholar]
  37. Cobb JA, Schleker T, Rojas V, Bjergbaek L, Tercero JA, Gasser SM. 37.  2005. Replisome instability, fork collapse, and gross chromosomal rearrangements arise synergistically from Mec1 kinase and RecQ helicase mutations. Genes Dev 19:3055–69 [Google Scholar]
  38. Colosio A, Frattini C, Pellicanò G, Villa-Hernández S, Bermejo R. 38.  2016. Nucleolytic processing of aberrant replication intermediates by an Exo1-Dna2-Sae2 axis counteracts fork collapse-driven chromosome instability. Nucleic Acids Res 44:10676–90 [Google Scholar]
  39. Cortez D. 39.  2015. Preventing replication fork collapse to maintain genome integrity. DNA Repair 32:149–57 [Google Scholar]
  40. Costantino L, Sotiriou SK, Rantala JK, Magin S, Mladenov E. 40.  et al. 2014. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science 343:88–91 [Google Scholar]
  41. Costanzo V. 41.  2011. Brca2, Rad51 and Mre11: performing balancing acts on replication forks. DNA Repair 10:1060–65 [Google Scholar]
  42. Costanzo V, Robertson K, Bibikova M, Kim E, Grieco D. 42.  et al. 2001. Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication. Mol. Cell 8:137–47 [Google Scholar]
  43. Cotta-Ramusino C, Fachinetti D, Lucca C, Doksani Y, Lopes M. 43.  et al. 2005. Exo1 processes stalled replication forks and counteracts fork reversal in checkpoint-defective cells. Mol. Cell 17:153–59 [Google Scholar]
  44. Couch FB, Bansbach CE, Driscoll R, Luzwick JW, Glick GG. 44.  et al. 2013. ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes Dev 27:1610–23 [Google Scholar]
  45. Coverley D, Laman H, Laskey RA. 45.  2002. Distinct roles for cyclins E and A during DNA replication complex assembly and activation. Nat. Cell Biol. 4:523–28 [Google Scholar]
  46. Crow YJ, Manel N. 46.  2015. Aicardi-Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15:429–40 [Google Scholar]
  47. Daddacha W, Koyen AE, Bastien AJ, Head PS, Dhere VR. 47.  et al. 2017. SAMHD1 promotes DNA end resection to facilitate DNA repair by homologous recombination. Cell Rep 20:1921–35 [Google Scholar]
  48. Daigaku Y, Davies AA, Ulrich HD. 48.  2010. Ubiquitin-dependent DNA damage bypass is separable from genome replication. Nature 465:951–55 [Google Scholar]
  49. De Piccoli G Katou Y, Itoh T, Nakato R, Shirahige K, Labib K. 49.  2012. Replisome stability at defective DNA replication forks is independent of S phase checkpoint kinases. Mol. Cell 45:696–704 [Google Scholar]
  50. Dehe PM, Gaillard PH. 50.  2017. Control of structure-specific endonucleases to maintain genome stability. Nat. Rev. Mol. Cell Biol. 18:315–30 [Google Scholar]
  51. Dilley RL, Verma P, Cho NW, Winters HD, Wondisford AR, Greenberg RA. 51.  2016. Break-induced telomere synthesis underlies alternative telomere maintenance. Nature 539:54–58 [Google Scholar]
  52. Ding X, Ray Chaudhuri A, Callen E, Pang Y, Biswas K. 52.  et al. 2016. Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies. Nat. Commun. 7:12425 [Google Scholar]
  53. Donnianni RA, Symington LS. 53.  2013. Break-induced replication occurs by conservative DNA synthesis. PNAS 110:13475–80 [Google Scholar]
  54. Duda H, Arter M, Gloggnitzer J, Teloni F, Wild P. 54.  et al. 2016. A mechanism for controlled breakage of under-replicated chromosomes during mitosis. Dev. Cell 39:740–55 [Google Scholar]
  55. Dungrawala H, Rose KL, Bhat KP, Mohni KN, Glick GG. 55.  et al. 2015. The replication checkpoint prevents two types of fork collapse without regulating replisome stability. Mol. Cell 59:998–1010 [Google Scholar]
  56. Elvers I, Johansson F, Groth P, Erixon K, Helleday T. 56.  2011. UV stalled replication forks restart by re-priming in human fibroblasts. Nucleic Acids Res 39:7049–57 [Google Scholar]
  57. Erdal E, Haider S, Rehwinkel J, Harris AL, McHugh PJ. 57.  2017. A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1. Genes Dev 31:353–69 [Google Scholar]
  58. Evrin C, Clarke P, Zech J, Lurz R, Sun J. 58.  et al. 2009. A double-hexameric MCM2–7 complex is loaded onto origin DNA during licensing of eukaryotic DNA replication. PNAS 106:20240–45 [Google Scholar]
  59. Feng S, Zhao Y, Xu Y, Ning S, Huo W. 59.  et al. 2016. Ewing tumor-associated antigen 1 interacts with replication protein A to promote restart of stalled replication forks. J. Biol. Chem. 291:21956–62 [Google Scholar]
  60. Froget B, Blaisonneau J, Lambert S, Baldacci G. 60.  2008. Cleavage of stalled forks by fission yeast Mus81/Eme1 in absence of DNA replication checkpoint. Mol. Biol. Cell 19:445–56 [Google Scholar]
  61. Fu H, Martin MM, Regairaz M, Huang L, You Y. 61.  et al. 2015. The DNA repair endonuclease Mus81 facilitates fast DNA replication in the absence of exogenous damage. Nat. Commun. 6:6746 [Google Scholar]
  62. Gambus A, Jones RC, Sanchez-Diaz A, Kanemaki M, van Deursen F. 62.  et al. 2006. GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks. Nat. Cell Biol. 8:358–66 [Google Scholar]
  63. Garcia-Gómez S, Reyes A, Martinez-Jiménez MI, Chocrón ES, Mourón S. 63.  et al. 2013. PrimPol, an archaic primase/polymerase operating in human cells. Mol. Cell 52:541–53 [Google Scholar]
  64. Gari K, Décaillet C, Delannoy M, Wu L, Constantinou A. 64.  2008. Remodeling of DNA replication structures by the branch point translocase FANCM. PNAS 105:16107–12 [Google Scholar]
  65. Garner E, Kim Y, Lach FP, Kottemann MC, Smogorzewska A. 65.  2013. Human GEN1 and the SLX4-associated nucleases MUS81 and SLX1 are essential for the resolution of replication-induced Holliday junctions. Cell Rep 5:207–15 [Google Scholar]
  66. Gasser S, Zhang WYL, Tan NYJ, Tripathi S, Suter MA. 66.  et al. 2017. Sensing of dangerous DNA. Mech. Ageing Dev. 165:33–46 [Google Scholar]
  67. Ge XQ, Blow JJ. 67.  2010. Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories. J. Cell Biol. 191:1285–97 [Google Scholar]
  68. Ghosal G, Chen J. 68.  2013. DNA damage tolerance: a double-edged sword guarding the genome. Transl. Cancer Res. 2:107–29 [Google Scholar]
  69. González-Prieto R, Muñoz-Cabello AM, Cabello-Lobato MJ, Prado F. 69.  2013. Rad51 replication fork recruitment is required for DNA damage tolerance. EMBO J 32:1307–21 [Google Scholar]
  70. Gravel S, Chapman JR, Magill C, Jackson SP. 70.  2008. DNA helicases Sgs1 and BLM promote DNA double-strand break resection. Genes Dev 22:2767–72 [Google Scholar]
  71. Guillemette S, Serra RW, Peng M, Hayes JA, Konstantinopoulos PA. 71.  et al. 2015. Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4. Genes Dev 29:489–94 [Google Scholar]
  72. Haahr P, Hoffmann S, Tollenaere MA, Ho T, Toledo LI. 72.  et al. 2016. Activation of the ATR kinase by the RPA-binding protein ETAA1. Nat. Cell Biol. 18:1196–207 [Google Scholar]
  73. Halazonetis TD, Gorgoulis VG, Bartek J. 73.  2008. An oncogene-induced DNA damage model for cancer development. Science 319:1352–55 [Google Scholar]
  74. Hanada K, Budzowska M, Davies SL, van Drunen E, Onizawa H. 74.  et al. 2007. The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks. Nat. Struct. Mol. Biol. 14:1096–104 [Google Scholar]
  75. Härtlova A, Erttmann SF, Raffi FAM, Schmalz AM, Resch U. 75.  et al. 2015. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. Immunity 42:332–43 [Google Scholar]
  76. Hashimoto Y, Ray Chaudhuri A, Lopes M, Costanzo V. 76.  2010. Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis. Nat. Struct. Mol. Biol. 17:1305–11 [Google Scholar]
  77. Hashimoto Y, Puddu F, Costanzo V. 77.  2012. RAD51- and MRE11-dependent reassembly of uncoupled CMG helicase complex at collapsed replication forks. Nat. Struct. Mol. Biol. 19:17–24 [Google Scholar]
  78. Heller RC, Marians KJ. 78.  2006. Replication fork reactivation downstream of a blocked nascent leading strand. Nature 439:557–62 [Google Scholar]
  79. Higgs MR, Reynolds JJ, Winczura A, Blackford AN, Borel V. 79.  et al. 2015. BOD1L is required to suppress deleterious resection of stressed replication forks. Mol. Cell 59:462–77 [Google Scholar]
  80. Ho SSW, Zhang WYL, Tan NYJ, Khatoo M, Suter MA. 80.  et al. 2016. The DNA structure-specific endonuclease MUS81 mediates DNA sensor STING-dependent host rejection of prostate cancer cells. Immunity 44:1177–89 [Google Scholar]
  81. Huang J, Liu S, Bellani MA, Thazhathveetil AK, Ling C. 81.  et al. 2013. The DNA translocase FANCM/MHF promotes replication traverse of DNA interstrand crosslinks. Mol. Cell 52:434–46 [Google Scholar]
  82. Ilves I, Petojevic T, Pesavento JJ, Botchan MR. 82.  2010. Activation of the MCM2–7 helicase by association with Cdc45 and GINS proteins. Mol. Cell 37:247–58 [Google Scholar]
  83. Jazayeri A, Balestrini A, Garner E, Haber JE, Costanzo V. 83.  2008. Mre11–Rad50–Nbs1‐dependent processing of DNA breaks generates oligonucleotides that stimulate ATM activity. EMBO J 27:1953–62 [Google Scholar]
  84. Kai M, Boddy MN, Russell P, Wang TS. 84.  2005. Replication checkpoint kinase Cds1 regulates Mus81 to preserve genome integrity during replication stress. Genes Dev 19:919–32 [Google Scholar]
  85. Kais Z, Rondinelli B, Holmes A, O'Leary C, Kozono D. 85.  et al. 2016. FANCD2 maintains fork stability in BRCA1/2-deficient tumors and promotes alternative end-joining DNA repair. Cell Rep 15:2488–99 [Google Scholar]
  86. Karras GI, Jentsch S. 86.  2010. The RAD6 DNA damage tolerance pathway operates uncoupled from the replication fork and is functional beyond S phase. Cell 141:255–67 [Google Scholar]
  87. Kile AC, Chavez DA, Bacal J, Eldirany S, Korzhnev DM. 87.  et al. 2015. HLTF's ancient HIRAN domain binds 3′ DNA ends to drive replication fork reversal. Mol. Cell 58:1090–100 [Google Scholar]
  88. Kim H-S, Nickoloff JA, Wu Y, Williamson EA, Sidhu GS. 88.  et al. 2017. Endonuclease EEPD1 is a gatekeeper for repair of stressed replication forks. J. Biol. Chem. 292:2795–804 [Google Scholar]
  89. Kim H-S, Williamson EA, Nickoloff JA, Hromas RA, Lee S-H. 89.  2017. Metnase mediates loading of exonuclease 1 onto single-strand overhang DNA for end resection at stalled replication forks. J. Biol. Chem. 292:1414–25 [Google Scholar]
  90. Kolinjivadi AM, Sannino V, De Antoni A Zadorozhny K, Kikenny M. 90.  et al. 2017. Smarcal1-mediated fork reversal triggers Mre11-dependent degradation of nascent DNA in the absence of Brca2 and Stable Rad51 nucleofilaments. Mol. Cell. 67:867–81.e7 [Google Scholar]
  91. Labib K, De Piccoli G. 91.  2011. Surviving chromosome replication: the many roles of the S-phase checkpoint pathway. Philos. Trans. R. Soc. B 366:3554–61 [Google Scholar]
  92. Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia C. 92.  et al. 2011. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474:654–57 [Google Scholar]
  93. Lambert S, Mizuno K, Blaisonneau J, Martineau S, Chanet R. 93.  et al. 2010. Homologous recombination restarts blocked replication forks at the expense of genome rearrangements by template exchange. Mol. Cell 39:346–59 [Google Scholar]
  94. Langerak P, Mejia-Ramirez E, Limbo O, Russell P. 94.  2011. Release of Ku and MRN from DNA ends by Mre11 nuclease activity and Ctp1 is required for homologous recombination repair of double-strand breaks. PLOS Genet 7:e1002271 [Google Scholar]
  95. Lee Y-C, Zhou Q, Chen J, Yuan J. 95.  2016. RPA-binding protein ETAA1 is an ATR activator involved in DNA replication stress response. Curr. Biol. 26:3257–68 [Google Scholar]
  96. Lemaçon D, Jackson J, Quinet A, Brickner JR, Li S. 96.  et al. 2017. MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells. Nat. Commun. 8:860 [Google Scholar]
  97. Lopes M, Foiani M, Sogo JM. 97.  2006. Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions. Mol. Cell 21:15–27 [Google Scholar]
  98. Lopez-Contreras AJ, Fernandez-Capetillo O. 98.  2010. The ATR barrier to replication-born DNA damage. DNA Repair 9:1249–55 [Google Scholar]
  99. Lossaint G, Larroque M, Ribeyre C, Bec N, Larroque C. 99.  et al. 2013. FANCD2 binds MCM proteins and controls replisome function upon activation of S phase checkpoint signaling. Mol. Cell 51:678–90 [Google Scholar]
  100. Luke-Glaser S, Luke B, Grossi S, Constantinou A. 100.  2010. FANCM regulates DNA chain elongation and is stabilized by S-phase checkpoint signalling. EMBO J 29:795–805 [Google Scholar]
  101. MacDougall CA, Byun TS, Van C, Yee M-c, Cimprich KA. 101.  2007. The structural determinants of checkpoint activation. Genes Dev 21:898–903 [Google Scholar]
  102. Macheret M, Halazonetis TD. 102.  2015. DNA replication stress as a hallmark of cancer. Annu. Rev. Pathol. Mech. Dis. 10:425–48 [Google Scholar]
  103. Mackenzie KJ, Carroll P, Lettice L, Tarnauskaitė Ž, Reddy K. 103.  et al. 2016. Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response. EMBO J 35:831–44 [Google Scholar]
  104. Mailand N, Gibbs-Seymour I, Bekker-Jensen S. 104.  2013. Regulation of PCNA–protein interactions for genome stability. Nat. Rev. Mol. Cell Biol. 14:269–82 [Google Scholar]
  105. Mayle R, Campbell IM, Beck CR, Yu Y, Wilson M. 105.  et al. 2015. Mus81 and converging forks limit the mutagenicity of replication fork breakage. Science 349:742–47 [Google Scholar]
  106. Meng X, Zhao X. 106.  2017. Replication fork regression and its regulation. FEMS Yeast Res. 17:fow110 [Google Scholar]
  107. Michl J, Zimmer J, Buffa FM, McDermott U, Tarsounas M. 107.  2016. FANCD2 limits replication stress and genome instability in cells lacking BRCA2. Nat. Struct. Mol. Biol. 23:755–57 [Google Scholar]
  108. Mijic S, Zellweger R, Chappidi N, Berti M, Jacobs K. 108.  et al. 2017. Replication fork reversal triggers fork degradation in BRCA2-defective cells. Nat. Commun. 8:859 [Google Scholar]
  109. Mimitou EP, Symington LS. 109.  2008. Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455:770–74 [Google Scholar]
  110. Minocherhomji S, Ying S, Bjerregaard VA, Bursomanno S, Aleliunaite A. 110.  et al. 2015. Replication stress activates DNA repair synthesis in mitosis. Nature 528:286–90 [Google Scholar]
  111. Morafraile EC, Diffley JF, Tercero JA, Segurado M. 111.  2015. Checkpoint-dependent RNR induction promotes fork restart after replicative stress. Sci. Rep. 5:7886 [Google Scholar]
  112. Morin I, Ngo H-P, Greenall A, Zubko MK, Morrice N, Lydall D. 112.  2008. Checkpoint-dependent phosphorylation of Exo1 modulates the DNA damage response. EMBO J 27:2400–10 [Google Scholar]
  113. Mourón S, Rodriguez-Acebes S, Martinez-Jiménez MI, Garcia-Gómez S, Chocrón S. 113.  et al. 2013. Repriming of DNA synthesis at stalled replication forks by human PrimPol. Nat. Struct. Mol. Biol. 20:1383–89 [Google Scholar]
  114. Muñoz-Galván S, Tous C, Blanco MG, Schwartz EK, Ehmsen KT. 114.  et al. 2012. Distinct roles of Mus81, Yen1, Slx1-Slx4, and Rad1 nucleases in the repair of replication-born double-strand breaks by sister chromatid exchange. Mol. Cell. Biol. 32:1592–603 [Google Scholar]
  115. Naim V, Wilhelm T, Debatisse M, Rosselli F. 115.  2013. ERCC1 and MUS81–EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis. Nat. Cell Biol. 15:1008–15 [Google Scholar]
  116. Nam EA, Cortez D. 116.  2011. ATR signalling: more than meeting at the fork. Biochem. J. 436:527–36 [Google Scholar]
  117. Neelsen KJ, Lopes M. 117.  2015. Replication fork reversal in eukaryotes: from dead end to dynamic response. Nat. Rev. Mol. Cell Biol. 16:207–20 [Google Scholar]
  118. Nguyen MO, Jalan M, Morrow CA, Osman F, Whitby MC. 118.  2015. Recombination occurs within minutes of replication blockage by RTS1 producing restarted forks that are prone to collapse. eLife 4:e04539 [Google Scholar]
  119. Nguyen VQ, Co C, Li JJ. 119.  2001. Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms. Nature 411:1068–73 [Google Scholar]
  120. Nicolette ML, Lee K, Guo Z, Rani M, Chow JM. 120.  et al. 2010. Mre11–Rad50–Xrs2 and Sae2 promote 5′ strand resection of DNA double-strand breaks. Nat. Struct. Mol. Biol. 17:1478–85 [Google Scholar]
  121. Nimonkar AV, Genschel J, Kinoshita E, Polaczek P, Campbell JL. 121.  et al. 2011. BLM-DNA2–RPA–MRN and EXO1–BLM–RPA–MRN constitute two DNA end resection machineries for human DNA break repair. Genes Dev 25:350–62 [Google Scholar]
  122. Niu H, Chung WH, Zhu Z, Kwon Y, Zhao W. 122.  et al. 2010. Mechanism of the ATP-dependent DNA end-resection machinery from S. cerevisiae. Nature 467:108–11 [Google Scholar]
  123. Pacek M, Tutter AV, Kubota Y, Takisawa H, Walter JC. 123.  2006. Localization of MCM2–7, Cdc45, and GINS to the site of DNA unwinding during eukaryotic DNA replication. Mol. Cell 21:581–87 [Google Scholar]
  124. Pacek M, Walter JC. 124.  2004. A requirement for MCM7 and Cdc45 in chromosome unwinding during eukaryotic DNA replication. EMBO J 23:3667–76 [Google Scholar]
  125. Pages V, Fuchs RP. 125.  2003. Uncoupling of leading- and lagging-strand DNA replication during lesion bypass in vivo. Science 300:1300–3 [Google Scholar]
  126. Paludan SR. 126.  2015. Activation and regulation of DNA-driven immune responses. Microbiol. Mol. Biol. Rev. 79:225–41 [Google Scholar]
  127. Pardo B, Crabbé L, Pasero P. 127.  2017. Signaling pathways of replication stress in yeast. FEMS Yeast Res. 17fow101 [Google Scholar]
  128. Pasero P, Braguglia D, Gasser SM. 128.  1997. ORC-dependent and origin-specific initiation of DNA replication at defined foci in isolated yeast nuclei. Genes Dev 11:1504–18 [Google Scholar]
  129. Patro BS, Frøhlich R, Bohr VA, Stevnsner T. 129.  2011. WRN helicase regulates the ATR–CHK1-induced S-phase checkpoint pathway in response to topoisomerase-I–DNA covalent complexes. J. Cell Sci. 124:3967–79 [Google Scholar]
  130. Paulsen RD, Cimprich KA. 130.  2007. The ATR pathway: fine-tuning the fork. DNA Repair 6:953–66 [Google Scholar]
  131. Pepe A, West SC. 131.  2014. MUS81–EME2 promotes replication fork restart. Cell Rep 7:1048–55 [Google Scholar]
  132. Pepe A, West SC. 132.  2014. Substrate specificity of the MUS81-EME2 structure selective endonuclease. Nucleic Acids Res 42:3833–45 [Google Scholar]
  133. Petermann E, Orta ML, Issaeva N, Schultz N, Helleday T. 133.  2010. Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Mol. Cell 37:492–502 [Google Scholar]
  134. Ray Chaudhuri A, Callen E, Ding X, Gogola E, Duarte AA. 134.  et al. 2016. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535:382–87 [Google Scholar]
  135. Ray Chaudhuri A, Hashimoto Y, Herrador R, Neelsen KJ, Fachinetti D. 135.  et al. 2012. Topoisomerase I poisoning results in PARP-mediated replication fork reversal. Nat. Struct. Mol. Biol. 19:417–23 [Google Scholar]
  136. Regairaz M, Zhang YW, Fu H, Agama KK, Tata N. 136.  et al. 2011. Mus81-mediated DNA cleavage resolves replication forks stalled by topoisomerase I–DNA complexes. J. Cell Biol. 195:739–49 [Google Scholar]
  137. Remus D, Beuron F, Tolun G, Griffith JD, Morris EP, Diffley JF. 137.  2009. Concerted loading of Mcm2–7 double hexamers around DNA during DNA replication origin licensing. Cell 139:719–30 [Google Scholar]
  138. Remus D, Blanchette M, Rio DC, Botchan MR. 138.  2005. CDK phosphorylation inhibits the DNA-binding and ATP-hydrolysis activities of the Drosophila origin recognition complex. J. Biol. Chem. 280:39740–51 [Google Scholar]
  139. Saini N, Ramakrishnan S, Elango R, Ayyar S, Zhang Y. 139.  et al. 2013. Migrating bubble during break-induced replication drives conservative DNA synthesis. Nature 502:389–92 [Google Scholar]
  140. Sale JE, Lehmann AR, Woodgate R. 140.  2012. Y-family DNA polymerases and their role in tolerance of cellular DNA damage. Nat. Rev. Mol. Cell Biol. 13:141–52 [Google Scholar]
  141. Sarbajna S, Davies D, West SC. 141.  2014. Roles of SLX1–SLX4, MUS81–EME1, and GEN1 in avoiding genome instability and mitotic catastrophe. Genes Dev 28:1124–36 [Google Scholar]
  142. Schlacher K, Christ N, Siaud N, Egashira A, Wu H, Jasin M. 142.  2011. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145:529–42 [Google Scholar]
  143. Schlacher K, Wu H, Jasin M. 143.  2012. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22:106–16 [Google Scholar]
  144. Seamon KJ, Sun Z, Shlyakhtenko LS, Lyubchenko YL, Stivers JT. 144.  2015. SAMHD1 is a single-stranded nucleic acid binding protein with no active site-associated nuclease activity. Nucleic Acids Res 43:6486–99 [Google Scholar]
  145. Segurado M, Diffley JFX. 145.  2008. Separate roles for the DNA damage checkpoint protein kinases in stabilizing DNA replication forks. Genes Dev 22:1816–27 [Google Scholar]
  146. Sharma S, Sommers JA, Gary RK, Friedrich-Heineken E, Hübscher U, Brosh RM Jr. 146.  2005. The interaction site of Flap Endonuclease-1 with WRN helicase suggests a coordination of WRN and PCNA. Nucleic Acids Res 33:6769–81 [Google Scholar]
  147. Shen YJ, Le Bert N, Chitre AA, Koo CX, Nga XH. 147.  et al. 2015. Genome-derived cytosolic DNA mediates type I interferon-dependent rejection of B cell lymphoma cells. Cell Rep 11:460–73 [Google Scholar]
  148. Shimura T, Torres MJ, Martin MM, Rao VA, Pommier Y. 148.  et al. 2008. Bloom's syndrome helicase and Mus81 are required to induce transient double-strand DNA breaks in response to DNA replication stress. J. Mol. Biol. 375:1152–64 [Google Scholar]
  149. Sogo JM, Lopes M, Foiani M. 149.  2002. Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects. Science 297:599–602 [Google Scholar]
  150. Sotiriou SK, Kamileri I, Lugli N, Evangelou K, Da-Re C. 150.  et al. 2016. Mammalian RAD52 functions in break-induced replication repair of collapsed DNA replication forks. Mol. Cell 64:1127–34 [Google Scholar]
  151. Spies J, Waizenegger A, Barton O, Sürder M, Wright WD. 151.  et al. 2016. Nek1 regulates Rad54 to orchestrate homologous recombination and replication fork stability. Mol. Cell 62:903–17 [Google Scholar]
  152. Stracker TH, Petrini JH. 152.  2011. The MRE11 complex: starting from the ends. Nat. Rev. Mol. Cell Biol. 12:90–103 [Google Scholar]
  153. Sturzenegger A, Burdova K, Kanagaraj R, Levikova M, Pinto C. 153.  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. 289:27314–26 [Google Scholar]
  154. Taglialatela A, Alvarez S, Leuzzi G, Sannino V, Ranjha L. 153a.  et al. 2017. Restoration of replication fork stability and genome integrity in BRCA1- and BRCA2-deficient cells by inactivation of SNF2-family fork remodelers. Mol. Cell 68:414–430.e8 [Google Scholar]
  155. Técher H, Koundrioukoff S, Carignon S, Wilhelm T, Millot GA. 154.  et al. 2016. Signaling from Mus81-Eme2-dependent DNA damage elicited by Chk1 deficiency modulates replication fork speed and origin usage. Cell Rep 14:1114–27 [Google Scholar]
  156. Tercero JA, Diffley JF. 155.  2001. Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint. Nature 412:553–57 [Google Scholar]
  157. Thangavel S, Berti M, Levikova M, Pinto C, Gomathinayagam S. 156.  et al. 2015. DNA2 drives processing and restart of reversed replication forks in human cells. J. Cell Biol. 208:545–62 [Google Scholar]
  158. Toledo LI, Altmeyer M, Rask M-B, Lukas C, Larsen DH. 157.  et al. 2013. ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell 155:1088–103 [Google Scholar]
  159. Tsang E, Miyabe I, Iraqui I, Zheng J, Lambert SAE, Carr AM. 158.  2014. The extent of error-prone replication restart by homologous recombination is controlled by Exo1 and checkpoint proteins. J. Cell Sci. 127:2983–94 [Google Scholar]
  160. Wang AT, Kim T, Wagner JE, Conti BA, Lach FP. 159.  et al. 2015. A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination. Mol. Cell 59:478–90 [Google Scholar]
  161. Wolf C, Rapp A, Berndt N, Staroske W, Schuster M. 160.  et al. 2016. RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. Nat. Commun. 7:11752 [Google Scholar]
  162. Wyatt HD, Sarbajna S, Matos J, West SC. 161.  2013. Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells. Mol. Cell 52:234–47 [Google Scholar]
  163. Xing M, Wang X, Palmai-Pallag T, Shen H, Helleday T. 162.  et al. 2015. Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response. Oncotarget 6:37638–46 [Google Scholar]
  164. Yang Y-G, Lindahl T, Barnes DE. 163.  2007. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131:873–86 [Google Scholar]
  165. Yao NY, O'Donnell M. 164.  2009. Replisome structure and conformational dynamics underlie fork progression past obstacles. Curr. Opin. Cell Biol. 21:336–43 [Google Scholar]
  166. Yeeles JT, Poli J, Marians KJ, Pasero P. 165.  2013. Rescuing stalled or damaged replication forks. Cold Spring Harb. Perspect. Biol. 5:a012815 [Google Scholar]
  167. Yeo JE, Lee EH, Hendrickson EA, Sobeck A. 166.  2014. CtIP mediates replication fork recovery in a FANCD2-regulated manner. Hum. Mol. Genet. 23:3695–705 [Google Scholar]
  168. Ying S, Hamdy FC, Helleday T. 167.  2012. Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1. Cancer Res 72:2814–21 [Google Scholar]
  169. Yuan J, Ghosal G, Chen J. 168.  2012. The HARP-like domain-containing protein AH2/ZRANB3 binds to PCNA and participates in cellular response to replication stress. Mol. Cell 47:410–21 [Google Scholar]
  170. Zellweger R, Dalcher D, Mutreja K, Berti M, Schmid JA. 169.  et al. 2015. Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells. J. Cell Biol. 208:563–79 [Google Scholar]
  171. Zeman MK, Cimprich KA. 170.  2014. Causes and consequences of replication stress. Nat. Cell Biol. 16:2–9 [Google Scholar]
  172. Zhang R, Sengupta S, Yang Q, Linke SP, Yanaihara N. 171.  et al. 2005. BLM helicase facilitates Mus81 endonuclease activity in human cells. Cancer Res 65:2526–31 [Google Scholar]
  173. Zheng L, Zhou M, Chai Q, Parrish J, Xue D. 172.  et al. 2005. Novel function of the flap endonuclease 1 complex in processing stalled DNA replication forks. EMBO Rep 6:83–89 [Google Scholar]
  174. Zhu Z, Chung WH, Shim EY, Lee SE, Ira G. 173.  2008. Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134:981–94 [Google Scholar]
  175. Zou L, Elledge SJ. 174.  2003. Sensing DNA damage through ATRIP recognition of RPA–ssDNA complexes. Science 300:1542–48 [Google Scholar]
/content/journals/10.1146/annurev-genet-120116-024745
Loading
/content/journals/10.1146/annurev-genet-120116-024745
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