1932

Abstract

Accurate DNA repair and replication are critical for genomic stability and cancer prevention. and its gene family are key regulators of DNA fidelity through diverse roles in double-strand break repair, replication stress, and meiosis. RAD51 is an ATPase that forms a nucleoprotein filament on single-stranded DNA. RAD51 has the function of finding and invading homologous DNA sequences to enable accurate and timely DNA repair. Its paralogs, which arose from ancient gene duplications of , have evolved to regulate and promote RAD51 function. Underscoring its importance, misregulation of RAD51, and its paralogs, is associated with diseases such as cancer and Fanconi anemia. In this review, we focus on the mammalian RAD51 structure and function and highlight the use of model systems to enable mechanistic understanding of RAD51 cellular roles. We also discuss how misregulation of the gene family members contributes to disease and consider new approaches to pharmacologically inhibit RAD51.

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2020-11-23
2024-03-29
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Literature Cited

  1. 1. 
    Abreu CM, Prakash R, Romanienko PJ, Roig I, Keeney S, Jasin M 2018. Shu complex SWS1-SWSAP1 promotes early steps in mouse meiotic recombination. Nat. Commun. 9:3961
    [Google Scholar]
  2. 2. 
    Ait Saada A, Lambert SAE, Carr AM 2018. Preserving replication fork integrity and competence via the homologous recombination pathway. DNA Repair 71:135–47
    [Google Scholar]
  3. 3. 
    Andriuskevicius T, Kotenko O, Makovets S 2018. Putting together and taking apart: assembly and disassembly of the Rad51 nucleoprotein filament in DNA repair and genome stability. Cell Stress 2:96–112
    [Google Scholar]
  4. 4. 
    Aten JA, Stap J, Krawczyk PM, van Oven CH, Hoebe RA et al. 2004. Dynamics of DNA double-strand breaks revealed by clustering of damaged chromosome domains. Science 303:92–95
    [Google Scholar]
  5. 5. 
    Baldock RA, Pressimone CA, Baird JM, Khodakov A, Luong TT et al. 2019. RAD51D splice variants and cancer-associated mutations reveal XRCC2 interaction to be critical for homologous recombination. DNA Repair 76:99–107
    [Google Scholar]
  6. 6. 
    Ball LG, Zhang K, Cobb JA, Boone C, Xiao W 2009. The yeast Shu complex couples error-free post-replication repair to homologous recombination. Mol. Microbiol. 73:89–102
    [Google Scholar]
  7. 7. 
    Barber LJ, Youds JL, Ward JD, McIlwraith MJ, O'Neil NJ et al. 2008. RTEL1 maintains genomic stability by suppressing homologous recombination. Cell 135:261–71
    [Google Scholar]
  8. 8. 
    Bayer FE, Deichsel S, Mahl P, Nagel AC 2020. Drosophila Xrcc2 regulates DNA double-strand repair in somatic cells. DNA Repair 88:102807
    [Google Scholar]
  9. 9. 
    Bell JC, Plank JL, Dombrowski CC, Kowalczykowski SC 2012. Direct imaging of RecA nucleation and growth on single molecules of SSB-coated ssDNA. Nature 491:274–78
    [Google Scholar]
  10. 10. 
    Bernstein KA, Reid RJ, Sunjevaric I, Demuth K, Burgess RC, Rothstein R 2011. The Shu complex, which contains Rad51 paralogues, promotes DNA repair through inhibition of the Srs2 anti-recombinase. Mol. Biol. Cell 22:1599–607
    [Google Scholar]
  11. 11. 
    Berti M, Ray Chaudhuri A, Thangavel S, Gomathinayagam S, Kenig S 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]
  12. 12. 
    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 3:1958–69
    [Google Scholar]
  13. 13. 
    Bhat KP, Cortez D. 2018. RPA and RAD51: fork reversal, fork protection, and genome stability. Nat. Struct. Mol. Biol. 25:446–53
    [Google Scholar]
  14. 14. 
    Bianchi J, Rudd SG, Jozwiakowski SK, Bailey LJ, Soura V et al. 2013. PrimPol bypasses UV photoproducts during eukaryotic chromosomal DNA replication. Mol. Cell 52:566–73
    [Google Scholar]
  15. 15. 
    Borgogno MV, Monti MR, Zhao W, Sung P, Argarana CE, Pezza RJ 2016. Tolerance of DNA mismatches in Dmc1 recombinase-mediated DNA strand exchange. J. Biol. Chem. 291:4928–38
    [Google Scholar]
  16. 16. 
    Branzei D, Szakal B. 2017. Building up and breaking down: mechanisms controlling recombination during replication. Crit. Rev. Biochem. Mol. Biol. 52:381–94
    [Google Scholar]
  17. 17. 
    Brouwer I, Moschetti T, Candelli A, Garcin EB, Modesti M et al. 2018. Two distinct conformational states define the interaction of human RAD51-ATP with single-stranded DNA. EMBO J 37:e98162
    [Google Scholar]
  18. 18. 
    Brown MS, Bishop DK. 2014. DNA strand exchange and RecA homologs in meiosis. Cold Spring Harb. Perspect. Biol. 7:a016659
    [Google Scholar]
  19. 19. 
    Brown MS, Grubb J, Zhang A, Rust MJ, Bishop DK 2015. Small Rad51 and Dmc1 complexes often co-occupy both ends of a meiotic DNA double strand break. PLOS Genet 11:e1005653
    [Google Scholar]
  20. 20. 
    Budke B, Lv W, Kozikowski AP, Connell PP 2016. Recent developments using small molecules to target RAD51: how to best modulate RAD51 for anticancer therapy. ? ChemMedChem 11:2468–73
    [Google Scholar]
  21. 21. 
    Bugreev DV, Rossi MJ, Mazin AV 2011. Cooperation of RAD51 and RAD54 in regression of a model replication fork. Nucleic Acids Res 39:2153–64
    [Google Scholar]
  22. 22. 
    Buisson R, Dion-Cote AM, Coulombe Y, Launay H, Cai H et al. 2010. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat. Struct. Mol. Biol. 17:1247–54
    [Google Scholar]
  23. 23. 
    Busygina V, Sehorn MG, Shi IY, Tsubouchi H, Roeder GS, Sung P 2008. Hed1 regulates Rad51-mediated recombination via a novel mechanism. Genes Dev 22:786–95
    [Google Scholar]
  24. 24. 
    Carreira A, Hilario J, Amitani I, Baskin RJ, Shivji MK et al. 2009. The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51. Cell 136:1032–43
    [Google Scholar]
  25. 25. 
    Carreira A, Kowalczykowski SC. 2011. Two classes of BRC repeats in BRCA2 promote RAD51 nucleoprotein filament function by distinct mechanisms. PNAS 108:10448–53
    [Google Scholar]
  26. 26. 
    Charlot F, Chelysheva L, Kamisugi Y, Vrielynck N, Guyon A et al. 2014. RAD51B plays an essential role during somatic and meiotic recombination in Physcomitrella. Nucleic Acids Res 42:11965–78
    [Google Scholar]
  27. 27. 
    Chen H, Lisby M, Symington LS 2013. RPA coordinates DNA end resection and prevents formation of DNA hairpins. Mol. Cell 50:589–600
    [Google Scholar]
  28. 28. 
    Chintapalli SV, Bhardwaj G, Babu J, Hadjiyianni L, Hong Y et al. 2013. Reevaluation of the evolutionary events within recA/RAD51 phylogeny. BMC Genom 14:240
    [Google Scholar]
  29. 29. 
    Cloud V, Chan YL, Grubb J, Budke B, Bishop DK 2012. Rad51 is an accessory factor for Dmc1-mediated joint molecule formation during meiosis. Science 337:1222–25
    [Google Scholar]
  30. 30. 
    Cooper DL, Lovett ST. 2016. Recombinational branch migration by the RadA/Sms paralog of RecA in Escherichia coli. . eLife 5:e10807
    [Google Scholar]
  31. 31. 
    Cortez D. 2019. Replication-coupled DNA repair. Mol. Cell 74:866–76
    [Google Scholar]
  32. 32. 
    Costantino L, Sotiriou SK, Rantala JK, Magin S, Mladenov E et al. 2014. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science 343:88–91
    [Google Scholar]
  33. 33. 
    Crickard JB, Kaniecki K, Kwon Y, Sung P, Greene EC 2018. Meiosis-specific recombinase Dmc1 is a potent inhibitor of the Srs2 antirecombinase. PNAS 115:E10041–48
    [Google Scholar]
  34. 34. 
    Crickard JB, Kaniecki K, Kwon Y, Sung P, Greene EC 2018. Spontaneous self-segregation of Rad51 and Dmc1 DNA recombinases within mixed recombinase filaments. J. Biol. Chem. 293:4191–200
    [Google Scholar]
  35. 35. 
    Dray E, Etchin J, Wiese C, Saro D, Williams GJ et al. 2010. Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2. Nat. Struct. Mol. Biol. 17:1255–59
    [Google Scholar]
  36. 36. 
    Fugger K, Mistrik M, Danielsen JR, Dinant C, Falck J et al. 2009. Human Fbh1 helicase contributes to genome maintenance via pro- and anti-recombinase activities. J. Cell Biol. 186:655–63
    [Google Scholar]
  37. 37. 
    Fumasoni M, Zwicky K, Vanoli F, Lopes M, Branzei D 2015. Error-free DNA damage tolerance and sister chromatid proximity during DNA replication rely on the Polα/Primase/Ctf4 complex. Mol. Cell 57:812–23
    [Google Scholar]
  38. 38. 
    Gachechiladze M, Skarda J, Soltermann A, Joerger M 2017. RAD51 as a potential surrogate marker for DNA repair capacity in solid malignancies. Int. J. Cancer 141:1286–94
    [Google Scholar]
  39. 39. 
    Gaines WA, Godin SK, Kabbinavar FF, Rao T, VanDemark AP et al. 2015. Promotion of presynaptic filament assembly by the ensemble of S. cerevisiae Rad51 paralogues with Rad52. Nat. Commun. 6:7834
    [Google Scholar]
  40. 40. 
    Game JC, Mortimer RK. 1974. A genetic study of X-ray sensitive mutants in yeast. Mutat. Res. 24:281–92
    [Google Scholar]
  41. 41. 
    Garcia-Gomez S, Reyes A, Martinez-Jimenez MI, Chocron ES, Mouron S et al. 2013. PrimPol, an archaic primase/polymerase operating in human cells. Mol. Cell 52:541–53
    [Google Scholar]
  42. 42. 
    Garcin EB, Gon S, Sullivan MR, Brunette GJ, Cian A et al. 2019. Differential requirements for the RAD51 paralogs in genome repair and maintenance in human cells. PLOS Genet 15:e1008355
    [Google Scholar]
  43. 43. 
    Giannattasio M, Zwicky K, Follonier C, Foiani M, Lopes M, Branzei D 2014. Visualization of recombination-mediated damage bypass by template switching. Nat. Struct. Mol. Biol. 21:884–92
    [Google Scholar]
  44. 44. 
    Godin SK, Sullivan MR, Bernstein KA 2016. Novel insights into RAD51 activity and regulation during homologous recombination and DNA replication. Biochem. Cell Biol. 94:407–18
    [Google Scholar]
  45. 45. 
    Godin SK, Wier A, Kabbinavar F, Bratton-Palmer DS, Ghodke H et al. 2013. The Shu complex interacts with Rad51 through the Rad51 paralogues Rad55-Rad57 to mediate error-free recombination. Nucleic Acids Res 41:4525–34
    [Google Scholar]
  46. 46. 
    Godin SK, Zhang Z, Westmoreland JW, Lee AG, Mihalevic MJ et al. 2016. The Shu complex promotes error-free tolerance of alkylation-induced base-excision repair products. Nucleic Acids Res 30:8199–215
    [Google Scholar]
  47. 47. 
    Graneli A, Yeykal CC, Robertson RB, Greene EC 2006. Long-distance lateral diffusion of human Rad51 on double-stranded DNA. PNAS 103:1221–26
    [Google Scholar]
  48. 48. 
    Grishchuk AL, Kohli J. 2003. Five RecA-like proteins of Schizosaccharomyces pombe are involved in meiotic recombination. Genetics 165:1031–43
    [Google Scholar]
  49. 49. 
    Haber JE. 2018. DNA repair: the search for homology. Bioessays 40:e1700229
    [Google Scholar]
  50. 50. 
    Haldenby S, White MF, Allers T 2009. RecA family proteins in archaea: RadA and its cousins. Biochem. Soc. Trans. 37:102–7
    [Google Scholar]
  51. 51. 
    Hashimoto Y, Puddu F, Costanzo V 2011. RAD51- and MRE11-dependent reassembly of uncoupled CMG helicase complex at collapsed replication forks. Nat. Struct. Mol. Biol. 19:17–24
    [Google Scholar]
  52. 52. 
    Hengel SR, Spies MA, Spies M 2017. Small-molecule inhibitors targeting DNA repair and DNA repair deficiency in research and cancer therapy. Cell Chem. Biol. 24:1101–19
    [Google Scholar]
  53. 53. 
    Her J, Bunting SF. 2018. How cells ensure correct repair of DNA double-strand breaks. J. Biol. Chem. 293:10502–11
    [Google Scholar]
  54. 54. 
    Herzberg K, Bashkirov VI, Rolfsmeier M, Haghnazari E, McDonald WH et al. 2006. Phosphorylation of Rad55 on serines 2, 8, and 14 is required for efficient homologous recombination in the recovery of stalled replication forks. Mol. Cell. Biol. 26:8396–409
    [Google Scholar]
  55. 55. 
    Higgins NP, Kato K, Strauss B 1976. A model for replication repair in mammalian cells. J. Mol. Biol. 101:417–25
    [Google Scholar]
  56. 56. 
    Higgs MR, Reynolds JJ, Winczura A, Blackford AN, Borel V et al. 2015. BOD1L is required to suppress deleterious resection of stressed replication forks. Mol. Cell 59:462–77
    [Google Scholar]
  57. 57. 
    Hilario J, Amitani I, Baskin RJ, Kowalczykowski SC 2009. Direct imaging of human Rad51 nucleoprotein dynamics on individual DNA molecules. PNAS 106:361–68
    [Google Scholar]
  58. 58. 
    Hong S, Kim KP. 2013. Shu1 promotes homolog bias of meiotic recombination in Saccharomyces cerevisiae. Mol. . Cells 36:446–54
    [Google Scholar]
  59. 59. 
    Hunter N. 2015. Meiotic recombination: the essence of heredity. Cold Spring Harb. Perspect. Biol. 7:a016618
    [Google Scholar]
  60. 60. 
    Islam MN, Fox D 3rd, Guo R, Enomoto T, Wang W 2010. RecQL5 promotes genome stabilization through two parallel mechanisms—interacting with RNA polymerase II and acting as a helicase. Mol. Cell. Biol. 30:2460–72
    [Google Scholar]
  61. 61. 
    Karanam K, Kafri R, Loewer A, Lahav G 2012. Quantitative live cell imaging reveals a gradual shift between DNA repair mechanisms and a maximal use of HR in mid S phase. Mol. Cell 47:320–29
    [Google Scholar]
  62. 62. 
    Keeney S. 2008. Spo11 and the formation of DNA double-strand breaks in meiosis. Genome Dyn. Stab. 2:81–123
    [Google Scholar]
  63. 63. 
    Khasanov FK, Salakhova AF, Chepurnaja OV, Korolev VG, Bashkirov VI 2004. Identification and characterization of the rlp1+, the novel Rad51 paralog in the fission yeast Schizosaccharomyces pombe. . DNA Repair 3:1363–74
    [Google Scholar]
  64. 64. 
    Kolinjivadi AM, Sannino V, De Antoni A, Zadorozhny K, Kilkenny M 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]
  65. 65. 
    Kramara J, Osia B, Malkova A 2018. Break-induced replication: the where, the why, and the how. Trends Genet 34:518–31
    [Google Scholar]
  66. 66. 
    Lao JP, Hunter N. 2010. Trying to avoid your sister. PLOS Biol 8:e1000519
    [Google Scholar]
  67. 67. 
    Laurini E, Marson D, Fermeglia A, Aulic S, Fermeglia M, Pricl S 2020. Role of Rad51 and DNA repair in cancer: a molecular perspective. Pharmacol. Ther. 208:107492
    [Google Scholar]
  68. 68. 
    Lee JY, Terakawa T, Qi Z, Steinfeld JB, Redding S et al. 2015. Base triplet stepping by the Rad51/RecA family of recombinases. Science 349:977–81
    [Google Scholar]
  69. 69. 
    Lemacon D, Jackson J, Quinet A, Brickner JR, Li S 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]
  70. 70. 
    Lin Z, Kong H, Nei M, Ma H 2006. Origins and evolution of the recA/RAD51 gene family: evidence for ancient gene duplication and endosymbiotic gene transfer. PNAS 103:10328–33
    [Google Scholar]
  71. 71. 
    Liu J, Renault L, Veaute X, Fabre F, Stahlberg H, Heyer WD 2011. Rad51 paralogues Rad55–Rad57 balance the antirecombinase Srs2 in Rad51 filament formation. Nature 479:245–48
    [Google Scholar]
  72. 72. 
    Liu T, Huang J. 2016. DNA end resection: facts and mechanisms. Genom. Proteom. Bioinform. 14:126–30
    [Google Scholar]
  73. 73. 
    Liu T, Wan L, Wu Y, Chen J, Huang J 2011. hSWS1⋅SWSAP1 is an evolutionarily conserved complex required for efficient homologous recombination repair. J. Biol. Chem. 286:41758–66
    [Google Scholar]
  74. 74. 
    Lopes A, Amarir-Bouhram J, Faure G, Petit M-A, Guerois R 2010. Detection of novel recombinases in bacteriophage genomes unveils Rad52, Rad51 and Gp2.5 remote homologs. Nucleic Acids Res 38:3952–62
    [Google Scholar]
  75. 75. 
    Mankouri HW, Ngo HP, Hickson ID 2007. Shu proteins promote the formation of homologous recombination intermediates that are processed by Sgs1-Rmi1-Top3. Mol. Biol. Cell 18:4062–73
    [Google Scholar]
  76. 76. 
    Martin V, Chahwan C, Gao H, Blais V, Wohlschlegel J et al. 2006. Sws1 is a conserved regulator of homologous recombination in eukaryotic cells. EMBO J 25:2564–74
    [Google Scholar]
  77. 77. 
    Martino J, Bernstein KA. 2016. The Shu complex is a conserved regulator of homologous recombination. FEMS Yeast Res 16:fow073
    [Google Scholar]
  78. 78. 
    Martino J, Brunette GJ, Barroso-Gonzalez J, Moiseeva TN, Smith CM et al. 2019. The human Shu complex functions with PDS5B and SPIDR to promote homologous recombination. Nucleic Acids Res 47:1051–65
    [Google Scholar]
  79. 79. 
    Mason JM, Chan YL, Weichselbaum RW, Bishop DK 2019. Non-enzymatic roles of human RAD51 at stalled replication forks. Nat. Commun. 10:4410
    [Google Scholar]
  80. 80. 
    Masson JY, Tarsounas MC, Stasiak AZ, Stasiak A, Shah R et al. 2001. Identification and purification of two distinct complexes containing the five RAD51 paralogs. Genes Dev 15:3296–307
    [Google Scholar]
  81. 81. 
    Matsuzaki K, Kondo S, Ishikawa T, Shinohara A 2019. Human RAD51 paralogue SWSAP1 fosters RAD51 filament by regulating the anti-recombinase FIGNL1 AAA+ ATPase. Nat. Commun. 10:1407
    [Google Scholar]
  82. 82. 
    Mayle R, Campbell IM, Beck CR, Yu Y, Wilson M et al. 2015. Mus81 and converging forks limit the mutagenicity of replication fork breakage. Science 349:742–47
    [Google Scholar]
  83. 83. 
    McClendon TB, Sullivan MR, Bernstein KA, Yanowitz JL 2016. Promotion of homologous recombination by SWS-1 in complex with RAD-51 paralogs in Caenorhabditis elegans. . Genetics 203:133–45
    [Google Scholar]
  84. 84. 
    Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B et al. 2010. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat. Genet. 42:410–14
    [Google Scholar]
  85. 85. 
    Mijic S, Zellweger R, Chappidi N, Berti M, Jacobs K et al. 2017. Replication fork reversal triggers fork degradation in BRCA2-defective cells. Nat. Commun. 8:859
    [Google Scholar]
  86. 86. 
    Mishra A, Saxena S, Kaushal A, Nagaraju G 2018. RAD51C/XRCC3 facilitates mitochondrial DNA replication and maintains integrity of the mitochondrial genome. Mol. Cell. Biol. 38:e00489–17
    [Google Scholar]
  87. 87. 
    Moran NA, Mira A. 2001. The process of genome shrinkage in the obligate symbiont Buchnera aphidicola. . Genome Biol 2:research0054.1
    [Google Scholar]
  88. 88. 
    Morgan EA, Shah N, Symington LS 2002. The requirement for ATP hydrolysis by Saccharomyces cerevisiae Rad51 is bypassed by mating-type heterozygosity or RAD54 in high copy. Mol. Cell. Biol. 22:6336–43
    [Google Scholar]
  89. 89. 
    Nalepa G, Clapp DW. 2018. Fanconi anaemia and cancer: an intricate relationship. Nat. Rev. Cancer 18:168–85
    [Google Scholar]
  90. 90. 
    Neelsen KJ, Lopes M. 2015. Replication fork reversal in eukaryotes: from dead end to dynamic response. Nat. Rev. Mol. Cell Biol. 16:207–20
    [Google Scholar]
  91. 91. 
    Pannunzio NR, Watanabe G, Lieber MR 2018. Nonhomologous DNA end-joining for repair of DNA double-strand breaks. J. Biol. Chem. 293:10512–23
    [Google Scholar]
  92. 92. 
    Pastushok L, Fu Y, Lin L, Luo Y, DeCoteau JF et al. 2019. A novel cell-penetrating antibody fragment inhibits the DNA repair protein RAD51. Sci. Rep. 9:11227
    [Google Scholar]
  93. 93. 
    Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC et al. 2014. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin. Cancer Res. 20:764–75
    [Google Scholar]
  94. 94. 
    Petermann E, Orta ML, Issaeva N, Schultz N, Helleday T 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]
  95. 95. 
    Prado F. 2018. Homologous recombination: to fork and beyond. Genes 9:603
    [Google Scholar]
  96. 96. 
    Prakash R, Zhang Y, Feng W, Jasin M 2015. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb. Perspect. Biol. 7:a016600
    [Google Scholar]
  97. 97. 
    Qi W, Wang R, Chen H, Wang X, Xiao T et al. 2015. BRG1 promotes the repair of DNA double-strand breaks by facilitating the replacement of RPA with RAD51. J. Cell Sci. 128:317–30
    [Google Scholar]
  98. 98. 
    Qiu Y, Antony E, Doganay S, Koh HR, Lohman TM, Myong S 2013. Srs2 prevents Rad51 filament formation by repetitive motion on DNA. Nat. Commun. 4:2281
    [Google Scholar]
  99. 99. 
    Renkawitz J, Lademann CA, Kalocsay M, Jentsch S 2013. Monitoring homology search during DNA double-strand break repair in vivo. Mol. Cell 50:261–72
    [Google Scholar]
  100. 100. 
    Ristic D, Modesti M, van der Heijden T, van Noort J, Dekker C et al. 2005. Human Rad51 filaments on double- and single-stranded DNA: correlating regular and irregular forms with recombination function. Nucleic Acids Res 33:3292–302
    [Google Scholar]
  101. 101. 
    Rosenbaum JC, Bonilla B, Hengel SR, Mertz TM, Herken BW et al. 2019. The Rad51 paralogs facilitate a novel DNA strand specific damage tolerance pathway. Nat. Commun. 10:3515
    [Google Scholar]
  102. 102. 
    Sage JM, Gildemeister OS, Knight KL 2010. Discovery of a novel function for human Rad51: maintenance of the mitochondrial genome. J. Biol. Chem. 285:18984–90
    [Google Scholar]
  103. 103. 
    Sasaki MS, Takata M, Sonoda E, Tachibana A, Takeda S 2004. Recombination repair pathway in the maintenance of chromosomal integrity against DNA interstrand crosslinks. Cytogenet. Genome Res. 104:28–34
    [Google Scholar]
  104. 104. 
    Sasanuma H, Tawaramoto MS, Lao JP, Hosaka H, Sanda E et al. 2013. A new protein complex promoting the assembly of Rad51 filaments. Nat. Commun. 4:1676
    [Google Scholar]
  105. 105. 
    Saxena S, Somyajit K, Nagaraju G 2018. XRCC2 regulates replication fork progression during dNTP alterations. Cell Rep 25:3273–82.e6
    [Google Scholar]
  106. 106. 
    Scheckenbach K, Baldus SE, Balz V, Freund M, Pakropa P et al. 2014. RAD51C—a new human cancer susceptibility gene for sporadic squamous cell carcinoma of the head and neck (HNSCC). Oral. Oncol. 50:196–99
    [Google Scholar]
  107. 107. 
    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 145:529–42
    [Google Scholar]
  108. 108. 
    Schlacher K, Wu H, Jasin M 2012. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22:106–16
    [Google Scholar]
  109. 109. 
    Schrank BR, Aparicio T, Li Y, Chang W, Chait BT et al. 2018. Nuclear ARP2/3 drives DNA break clustering for homology-directed repair. Nature 559:61–66
    [Google Scholar]
  110. 110. 
    Schwacha A, Kleckner N. 1997. Interhomolog bias during meiotic recombination: Meiotic functions promote a highly differentiated interhomolog-only pathway. Cell 90:1123–35
    [Google Scholar]
  111. 111. 
    Shigenobu S, Watanabe H, Hattori M, Sakaki Y, Ishikawa H 2000. Genome sequence of the endocellular bacterial symbiont of aphids Buchnera sp. APS. Nature 407:81–86
    [Google Scholar]
  112. 112. 
    Shinohara A, Gasior S, Ogawa T, Kleckner N, Bishop DK 1997. Saccharomyces cerevisiae recA homologues RAD51 and DMC1 have both distinct and overlapping roles in meiotic recombination. Genes Cells 2:615–29
    [Google Scholar]
  113. 113. 
    Shor E, Weinstein J, Rothstein R 2005. A genetic screen for top3 suppressors in Saccharomyces cerevisiae identifies SHU1, SHU2, PSY3 and CSM2: four genes involved in error-free DNA repair. Genetics 169:1275–89
    [Google Scholar]
  114. 114. 
    Short JM, Liu Y, Chen S, Soni N, Madhusudhan MS et al. 2016. High-resolution structure of the presynaptic RAD51 filament on single-stranded DNA by electron cryo-microscopy. Nucleic Acids Res 44:9017–30
    [Google Scholar]
  115. 115. 
    Silva MC, Morrical MD, Bryan KE, Averill AM, Dragon J et al. 2016. RAD51 variant proteins from human lung and kidney tumors exhibit DNA strand exchange defects. DNA Repair 42:44–55
    [Google Scholar]
  116. 116. 
    Somyajit K, Basavaraju S, Scully R, Nagaraju G 2013. ATM- and ATR-mediated phosphorylation of XRCC3 regulates DNA double-strand break-induced checkpoint activation and repair. Mol. Cell. Biol. 33:1830–44
    [Google Scholar]
  117. 117. 
    Somyajit K, Saxena S, Babu S, Mishra A, Nagaraju G 2015. Mammalian RAD51 paralogs protect nascent DNA at stalled forks and mediate replication restart. Nucleic Acids Res 43:9835–55
    [Google Scholar]
  118. 118. 
    Spirek M, Mlcouskova J, Belan O, Gyimesi M, Harami GM et al. 2018. Human RAD51 rapidly forms intrinsically dynamic nucleoprotein filaments modulated by nucleotide binding state. Nucleic Acids Res 46:3967–80
    [Google Scholar]
  119. 119. 
    Stark JM, Hu P, Pierce AJ, Moynahan ME, Ellis N, Jasin M 2002. ATP hydrolysis by mammalian RAD51 has a key role during homology-directed DNA repair. J. Biol. Chem. 277:20185–94
    [Google Scholar]
  120. 120. 
    Steinfeld JB, Belan O, Kwon Y, Terakawa T, Al-Zain A et al. 2019. Defining the influence of Rad51 and Dmc1 lineage-specific amino acids on genetic recombination. Genes Dev 33:1191–207
    [Google Scholar]
  121. 121. 
    Subramanyam S, Ismail M, Bhattacharya I, Spies M 2016. Tyrosine phosphorylation stimulates activity of human RAD51 recombinase through altered nucleoprotein filament dynamics. PNAS 113:E6045–54
    [Google Scholar]
  122. 122. 
    Sugiyama T, Kowalczykowski SC. 2002. Rad52 protein associates with replication protein A (RPA)-single-stranded DNA to accelerate Rad51-mediated displacement of RPA and presynaptic complex formation. J. Biol. Chem. 277:31663–72
    [Google Scholar]
  123. 123. 
    Sullivan MR, Bernstein KA. 2018. RAD-ical new insights into RAD51 regulation. Genes 9:629
    [Google Scholar]
  124. 124. 
    Sung P. 1997. Function of yeast Rad52 protein as a mediator between replication protein A and the Rad51 recombinase. J. Biol. Chem. 272:28194–97
    [Google Scholar]
  125. 125. 
    Sung P. 1997. Yeast Rad55 and Rad57 proteins form a heterodimer that functions with replication protein A to promote DNA strand exchange by Rad51 recombinase. Genes Dev 11:1111–21
    [Google Scholar]
  126. 126. 
    Sung P, Stratton SA. 1996. Yeast Rad51 recombinase mediates polar DNA strand exchange in the absence of ATP hydrolysis. J. Biol. Chem. 271:27983–86
    [Google Scholar]
  127. 127. 
    Symington LS. 2002. Role of RAD52 epistasis group genes in homologous recombination and double-strand break repair. Microbiol. Mol. Biol. Rev. 66:630–70
    [Google Scholar]
  128. 128. 
    Symington LS, Gautier J. 2011. Double-strand break end resection and repair pathway choice. Annu. Rev. Genet. 45:247–71
    [Google Scholar]
  129. 129. 
    Taglialatela A, Alvarez S, Leuzzi G, Sannino V, Ranjha L et al. 2017. Restoration of replication fork stability in BRCA1- and BRCA2-deficient cells by inactivation of SNF2-family fork remodelers. Mol. Cell 68:414–30.e8
    [Google Scholar]
  130. 130. 
    Tavares EM, Wright WD, Heyer WD, Le Cam E, Dupaigne P 2019. In vitro role of Rad54 in Rad51-ssDNA filament-dependent homology search and synaptic complexes formation. Nat. Commun. 10:4058
    [Google Scholar]
  131. 131. 
    Taylor MRG, Spirek M, Chaurasiya KR, Ward JD, Carzaniga R et al. 2015. Rad51 paralogs remodel pre-synaptic Rad51 filaments to stimulate homologous recombination. Cell 162:271–86
    [Google Scholar]
  132. 132. 
    Taylor MRG, Yeeles JTP. 2018. The initial response of a eukaryotic replisome to DNA damage. Mol. Cell 70:1067–80.e12
    [Google Scholar]
  133. 133. 
    Teixeira-Silva A, Ait Saada A, Hardy J, Iraqui I, Nocente MC et al. 2017. The end-joining factor Ku acts in the end-resection of double strand break-free arrested replication forks. Nat. Commun. 8:1982
    [Google Scholar]
  134. 134. 
    Thangavel S, Berti M, Levikova M, Pinto C, Gomathinayagam S et al. 2015. DNA2 drives processing and restart of reversed replication forks in human cells. J. Cell Biol. 208:545–62
    [Google Scholar]
  135. 135. 
    Tombline G, Fishel R. 2002. Biochemical characterization of the human RAD51 protein. I. ATP hydrolysis. J. Biol. Chem. 277:14417–25
    [Google Scholar]
  136. 136. 
    Turchick A, Liu Y, Zhao W, Cohen I, Glazer PM 2019. Synthetic lethality of a cell-penetrating anti-RAD51 antibody in PTEN-deficient melanoma and glioma cells. Oncotarget 10:1272–83
    [Google Scholar]
  137. 137. 
    Unk I, Hajdu I, Blastyak A, Haracska L 2010. Role of yeast Rad5 and its human orthologs, HLTF and SHPRH in DNA damage tolerance. DNA Repair 9:257–67
    [Google Scholar]
  138. 138. 
    van der Zon NL, Kanaar R, Wyman C 2018. Variation in RAD51 details a hub of functions: opportunities to advance cancer diagnosis and therapy. F1000Research 7:1453
    [Google Scholar]
  139. 139. 
    Wang AT, Kim T, Wagner JE, Conti BA, Lach FP 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]
  140. 140. 
    Ward A, Khanna KK, Wiegmans AP 2015. Targeting homologous recombination, new pre-clinical and clinical therapeutic combinations inhibiting RAD51. Cancer Treat. Rev. 41:35–45
    [Google Scholar]
  141. 141. 
    Wong AK, Pero R, Ormonde PA, Tavtigian SV, Bartel PL 1997. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2. J. Biol. . Chem 272:31941–44
    [Google Scholar]
  142. 142. 
    Wu D, Wu M, Halpern A, Rusch DB, Yooseph S et al. 2011. Stalking the fourth domain in metagenomic data: searching for, discovering, and interpreting novel, deep branches in marker gene phylogenetic trees. PLOS ONE 6:e18011
    [Google Scholar]
  143. 143. 
    Xu J, Zhao L, Xu Y, Zhao W, Sung P, Wang HW 2017. Cryo-EM structures of human RAD51 recombinase filaments during catalysis of DNA-strand exchange. Nat. Struct. Mol. Biol. 24:40–46
    [Google Scholar]
  144. 144. 
    Xu X, Ball L, Chen W, Tian X, Lambrecht A et al. 2013. The yeast Shu complex utilizes homologous recombination machinery for error-free lesion bypass via physical interaction with a Rad51 paralogue. PLOS ONE 8:e81371
    [Google Scholar]
  145. 145. 
    Yang H, Jeffrey PD, Miller J, Kinnucan E, Sun Y et al. 2002. BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297:1837–48
    [Google Scholar]
  146. 146. 
    Yu X, Jacobs SA, West SC, Ogawa T, Egelman EH 2001. Domain structure and dynamics in the helical filaments formed by RecA and Rad51 on DNA. PNAS 98:8419–24
    [Google Scholar]
  147. 147. 
    Zadorozhny K, Sannino V, Belan O, Mlcouskova J, Spirek M et al. 2017. Fanconi-anemia-associated mutations destabilize RAD51 filaments and impair replication fork protection. Cell Rep 21:333–40
    [Google Scholar]
  148. 148. 
    Zellweger R, Dalcher D, Mutreja K, Berti M, Schmid JA 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]
  149. 149. 
    Zeman MK, Cimprich KA. 2014. Causes and consequences of replication stress. Nat. Cell Biol. 16:2–9
    [Google Scholar]
  150. 150. 
    Zhang S, Wang L, Tao Y, Bai T, Lu R et al. 2017. Structural basis for the functional role of the Shu complex in homologous recombination. Nucleic Acids Res 45:13068–79
    [Google Scholar]
  151. 151. 
    Zhao W, Steinfeld JB, Liang F, Chen X, Maranon DG et al. 2017. BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing. Nature 550:360–65
    [Google Scholar]
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