3,092
Views
261
CrossRef citations to date
0
Altmetric
Review Article

Mechanism and regulation of DNA end resection in eukaryotes

Pages 195-212 | Received 12 Jan 2016, Accepted 28 Mar 2016, Published online: 20 Apr 2016

References

  • Adkins NL, Niu H, Sung P, Peterson CL. (2013). Nucleosome dynamics regulates DNA processing. Nat Struct Mol Biol 20:836–42.
  • Akamatsu Y, Murayama Y, Yamada T, et al. (2008). Molecular characterization of the role of the Schizosaccharomyces pombe nip1+/ctp1+ gene in DNA double-strand break repair in association with the Mre11–Rad50–Nbs1 complex. Mol Cell Biol 28:3639–51.
  • Alani E, Padmore R, Kleckner N. (1990). Analysis of wild-type and rad50 mutants of yeast suggests an intimate relationship between meiotic chromosome synapsis and recombination. Cell 61:419–36.
  • Andres SN, Appel CD, Westmoreland JW, et al. (2015). Tetrameric Ctp1 coordinates DNA binding and DNA bridging in DNA double-strand-break repair. Nat Struct Mol Biol 22:158–66.
  • Aylon Y, Liefshitz B, Kupiec M. (2004). The CDK regulates repair of double-strand breaks by homologous recombination during the cell cycle. EMBO J 23:4868–75.
  • Bae SH, Bae KH, Kim JA, Seo YS. (2001). RPA governs endonuclease switching during processing of Okazaki fragments in eukaryotes. Nature 412:456–61.
  • Balakrishnan L, Polaczek P, Pokharel S, et al. (2010). Dna2 exhibits a unique strand end-dependent helicase function. J Biol Chem 285:38861–8.
  • Barlow JH, Lisby M, Rothstein R. (2008). Differential regulation of the cellular response to DNA double-strand breaks in G1. Mol Cell 30:73–85.
  • Baroni E, Viscardi V, Cartagena-Lirola H, et al. (2004). The functions of budding yeast Sae2 in the DNA damage response require Mec1- and Tel1-dependent phosphorylation. Mol Cell Biol 24:4151–65.
  • Bennardo N, Cheng A, Huang N, Stark JM. (2008). Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet 4:e1000110.
  • Bergerat A, de Massy B, Gadelle D, et al. (1997). An atypical topoisomerase II from Archaea with implications for meiotic recombination. Nature 386:414–17.
  • Bernstein KA, Mimitou EP, Mihalevic MJ, et al. (2013). Resection activity of the Sgs1 helicase alters the affinity of DNA ends for homologous recombination proteins in Saccharomyces cerevisiae. Genetics 195:1241–51.
  • Bizard AH, Hickson ID. (2014). The dissolution of double Holliday junctions. Cold Spring Harb Perspect Biol 6:a016477.
  • Boersma V, Moatti N, Segura-Bayona S, et al. (2015). MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5′ end resection. Nature 521:537–40.
  • Bonetti D, Villa M, Gobbini E, et al. (2015). Escape of Sgs1 from Rad9 inhibition reduces the requirement for Sae2 and functional MRX in DNA end resection. EMBO Rep 16:351–61.
  • Boulton SJ, Jackson SP. (1998). Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing. EMBO J 17:1819–28.
  • Bouwman P, Aly A, Escandell JM, et al. (2010). 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol 17:688–95.
  • Bressan DA, Olivares HA, Nelms BE, Petrini JH. (1998). Alteration of N-terminal phosphoesterase signature motifs inactivates Saccharomyces cerevisiae Mre11. Genetics 150:591–600.
  • Brush GS, Morrow DM, Hieter P, Kelly TJ. (1996). The ATM homologue MEC1 is required for phosphorylation of replication protein A in yeast. Proc Natl Acad Sci USA 93:15075–80.
  • Budd ME, Campbell JL. (2009). Interplay of Mre11 nuclease with Dna2 plus Sgs1 in Rad51-dependent recombinational repair. PLoS One 4:e4267.
  • Buis J, Wu Y, Deng Y, et al. (2008). Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell 135:85–96.
  • Bunting SF, Callen E, Kozak ML, et al. (2012). BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. Mol Cell 46:125–35.
  • Bunting SF, Callen E, Wong N, et al. (2010). 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141:243–54.
  • Callen E, Di Virgilio M, Kruhlak MJ, et al. (2013). 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell 153:1266–80.
  • Cannavo E, Cejka P, Kowalczykowski SC. (2013). Relationship of DNA degradation by Saccharomyces cerevisiae exonuclease 1 and its stimulation by RPA and Mre11–Rad50–Xrs2 to DNA end resection. Proc Natl Acad Sci USA 110:E1661–8.
  • Cannavo E, Cejka P. (2014). Sae2 promotes dsDNA endonuclease activity within Mre11–Rad50–Xrs2 to resect DNA breaks. Nature 514:122–5.
  • Cannon B, Kuhnlein J, Yang SH, et al. (2013). Visualization of local DNA unwinding by Mre11/Rad50/Nbs1 using single-molecule FRET. Proc Natl Acad Sci USA 110:18868–73.
  • Carney JP, Maser RS, Olivares H, et al. (1998). The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93:477–86.
  • Cejka P, Cannavo E, Polaczek P, et al. (2010). DNA end resection by Dna2–Sgs1–RPA and its stimulation by Top3–Rmi1 and Mre11–Rad50–Xrs2. Nature 467:112–6.
  • Chapman JR, Barral P, Vannier JB, et al. (2013). RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol Cell 49:858–71.
  • Chapman JR, Jackson SP. (2008). Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage. EMBO Rep 9:795–801.
  • Chapman JR, Sossick AJ, Boulton SJ, Jackson SP. (2012). BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair. J Cell Sci 125:3529–34.
  • Chen H, Donnianni RA, Handa N, et al. (2015). Sae2 promotes DNA damage resistance by removing the Mre11–Rad50–Xrs2 complex from DNA and attenuating Rad53 signaling. Proc Natl Acad Sci USA 112:E1880–7.
  • Chen H, Lisby M, Symington LS. (2013). RPA coordinates DNA end resection and prevents formation of DNA hairpins. Mol Cell 50:589–600.
  • Chen L, Nievera CJ, Lee AY, Wu X. (2008). Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J Biol Chem 283:7713–20.
  • Chen PL, Liu F, Cai S, et al. (2005). Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency. Mol Cell Biol 25:3535–42.
  • Chen X, Cui D, Papusha A, et al. (2012). The Fun30 nucleosome remodeller promotes resection of DNA double-strand break ends. Nature 489:576–80.
  • Chen X, Niu H, Chung WH, et al. (2011). Cell cycle regulation of DNA double-strand break end resection by Cdk1-dependent Dna2 phosphorylation. Nat Struct Mol Biol 18:1015–19.
  • Chen X, Paudyal SC, Chin RI, You Z. (2013). PCNA promotes processive DNA end resection by Exo1. Nucleic Acids Res 41:9325–38.
  • Chiruvella KK, Liang Z, Wilson TE. (2013). Repair of double-strand breaks by end joining. Cold Spring Harbor Perspect Biol 5:a012757.
  • Ciccia A, Elledge SJ. (2010). The DNA damage response: making it safe to play with knives. Mol Cell 40:179–204.
  • Clerici M, Mantiero D, Guerini I, et al. (2008). The Yku70–Yku80 complex contributes to regulate double-strand break processing and checkpoint activation during the cell cycle. EMBO Rep 9:810–18.
  • Clerici M, Mantiero D, Lucchini G, Longhese MP. (2005). The Saccharomyces cerevisiae Sae2 protein promotes resection and bridging of double strand break ends. J Biol Chem 280:38631–8.
  • Clerici M, Mantiero D, Lucchini G, Longhese MP. (2006). The Saccharomyces cerevisiae Sae2 protein negatively regulates DNA damage checkpoint signalling. EMBO Rep 7:212–18.
  • Clerici M, Trovesi C, Galbiati A, et al. (2014). Mec1/ATR regulates the generation of single-stranded DNA that attenuates Tel1/ATM signaling at DNA ends. EMBO J 33:198–216.
  • Connelly JC, Kirkham LA, Leach DR. (1998). The SbcCD nuclease of Escherichia coli is a structural maintenance of chromosomes (SMC) family protein that cleaves hairpin DNA. Proc Natl Acad Sci USA 95:7969–74.
  • Corneo B, Wendland RL, Deriano L, et al. (2007). Rag mutations reveal robust alternative end joining. Nature 449:483–6.
  • Costelloe T, Louge R, Tomimatsu N, et al. (2012). The yeast Fun30 and human SMARCAD1 chromatin remodellers promote DNA end resection. Nature 489:581–4.
  • Davies OR, Forment JV, Sun M, et al. (2015). CtIP tetramer assembly is required for DNA-end resection and repair. Nat Struct Mol Biol 22:150–7.
  • Deng SK, Gibb B, de Almeida MJ, et al. (2014). RPA antagonizes microhomology-mediated repair of DNA double-strand breaks. Nat Struct Mol Biol 21:405–12.
  • Deng SK, Yin Y, Petes TD, Symington LS. (2015). Mre11–Sae2 and RPA collaborate to prevent palindromic gene amplification. Mol Cell 60:500–8.
  • Di Virgilio M, Callen E, Yamane A, et al. (2013). Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science 339:711–15.
  • Digilio FA, Pannuti A, Lucchesi JC, et al. (1996). Tosca: a Drosophila gene encoding a nuclease specifically expressed in the female germline. Dev Biol 178:90–100.
  • Dinkelmann M, Spehalski E, Stoneham T, et al. (2009). Multiple functions of MRN in end-joining pathways during isotype class switching. Nat Struct Mol Biol 16:808–13.
  • Dupre A, Boyer-Chatenet L, Sattler RM, et al. (2008). A forward chemical genetic screen reveals an inhibitor of the Mre11–Rad50–Nbs1 complex. Nat Chem Biol 4:119–25.
  • Eapen VV, Sugawara N, Tsabar M, et al. (2012). The Saccharomyces cerevisiae chromatin remodeler Fun30 regulates DNA end resection and checkpoint deactivation. Mol Cell Biol 32:4727–40.
  • Eid W, Steger M, El-Shemerly M, et al. (2010). DNA end resection by CtIP and exonuclease 1 prevents genomic instability. EMBO Rep 11:962–8.
  • El-Shemerly M, Janscak P, Hess D, et al. (2005). Degradation of human exonuclease 1b upon DNA synthesis inhibition. Cancer Res 65:3604–9.
  • Escribano-Diaz C, Orthwein A, Fradet-Turcotte A, et al. (2013). A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell 49:872–83.
  • Falck J, Coates J, Jackson SP. (2005). Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434:605–11.
  • Feng L, Fong KW, Wang J, et al. (2013). RIF1 counteracts BRCA1-mediated end resection during DNA repair. J Biol Chem 288:11135–43.
  • Ferrari M, Dibitetto D, De Gregorio G, et al. (2015). Functional interplay between the 53BP1-ortholog Rad9 and the Mre11 complex regulates resection, end-tethering and repair of a double-strand break. PLoS Genet 11:e1004928.
  • Foster SS, Balestrini A, Petrini JH. (2011). Functional interplay of the Mre11 nuclease and Ku in the response to replication-associated DNA damage. Mol Cell Biol 31:4379–89.
  • Fu Q, Chow J, Bernstein KA, et al. (2014). Phosphorylation-regulated transitions in an oligomeric state control the activity of the Sae2 DNA repair enzyme. Mol Cell Biol 34:778–93.
  • Furuse M, Nagase Y, Tsubouchi H, et al. (1998). Distinct roles of two separable in vitro activities of yeast Mre11 in mitotic and meiotic recombination. EMBO J 17:6412–25.
  • Garcia V, Phelps SE, Gray S, Neale MJ. (2011). Bidirectional resection of DNA double-strand breaks by Mre11 and Exo1. Nature 479:241–4.
  • Genschel J, Modrich P. (2003). Mechanism of 5′-directed excision in human mismatch repair. Mol Cell 12:1077–86.
  • Gobbini E, Cesena D, Galbiati A, et al. (2013). Interplays between ATM/Tel1 and ATR/Mec1 in sensing and signaling DNA double-strand breaks. DNA Repair (Amst) 12:791–9.
  • Gobbini E, Villa M, Gnugnoli M, et al. (2015). Sae2 function at DNA double-strand breaks is bypassed by dampening Tel1 or Rad53 activity. PLoS Genet 11:e1005685.
  • Gravel S, Chapman JR, Magill C, Jackson SP. (2008). DNA helicases Sgs1 and BLM promote DNA double-strand break resection. Genes Dev 22:2767–72.
  • Hardy J, Churikov D, Geli V, Simon MN. (2014). Sgs1 and Sae2 promote telomere replication by limiting accumulation of ssDNA. Nat Commun 5:5004.
  • Harrison JC, Haber JE. (2006). Surviving the breakup: the DNA damage checkpoint. Annu Rev Genet 40:209–35.
  • Hoa NN, Kobayashi J, Omura M, et al. (2015). BRCA1 and CtIP are both required to recruit Dna2 at double-strand breaks in homologous recombination. PLoS One 10:e0124495.
  • Hopfner KP, Craig L, Moncalian G, et al. (2002). The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair. Nature 418:562–6.
  • Hopfner KP. (2014). ATP puts the brake on DNA double-strand break repair: a new study shows that ATP switches the Mre11–Rad50–Nbs1 repair factor between signaling and processing of DNA ends. Bioessays 36:1170–8.
  • Hopkins BB, Paull TT. (2008). The P. furiosus mre11/rad50 complex promotes 5′ strand resection at a DNA double-strand break. Cell 135:250–60.
  • Huertas P, Cortes-Ledesma F, Sartori AA, et al. (2008). CDK targets Sae2 to control DNA-end resection and homologous recombination. Nature 455:689–92.
  • Huertas P, Jackson SP. (2009). Human CtIP mediates cell cycle control of DNA end resection and double strand break repair. J Biol Chem 284:9558–65.
  • Ira G, Pellicioli A, Balijja A, et al. (2004). DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431:1011–17.
  • Ismail IH, Gagne JP, Genois MM, et al. (2015). The RNF138 E3 ligase displaces Ku to promote DNA end resection and regulate DNA repair pathway choice. Nat Cell Biol 17:1446–57.
  • Kadyk LC, Hartwell LH. (1992). Sister chromatids are preferred over homologs as substrates for recombinational repair in Saccharomyces cerevisiae. Genetics 132:387–402.
  • Karanja KK, Cox SW, Duxin JP, et al. (2012). DNA2 and EXO1 in replication-coupled, homology-directed repair and in the interplay between HDR and the FA/BRCA network. Cell Cycle 11:3983–96.
  • Keeney S, Giroux CN, Kleckner N. (1997). Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell 88:375–84.
  • Kerr GW, Sarkar S, Arumugam P. (2012). How to halve ploidy: lessons from budding yeast meiosis. Cell Mol Life Sci 69:3037–51.
  • Kim HS, Vijayakumar S, Reger M, et al. (2008). Functional interactions between Sae2 and the Mre11 complex. Genetics 178:711–23.
  • Krasner DS, Daley JM, Sung P, Niu H. (2015). Interplay between Ku and replication protein A in the restriction of Exo1-mediated DNA break end resection. J Biol Chem 290:18806–16.
  • Krogh BO, Llorente B, Lam A, Symington LS. (2005). Mutations in Mre11 phosphoesterase motif I that impair Saccharomyces cerevisiae Mre11–Rad50–Xrs2 complex stability in addition to nuclease activity. Genetics 171:1561–70.
  • Lammens K, Bemeleit DJ, Mockel C, et al. (2011). The Mre11:Rad50 structure shows an ATP-dependent molecular clamp in DNA double-strand break repair. Cell 145:54–66.
  • Langerak P, Mejia-Ramirez E, Limbo O, Russell P. (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.
  • Lazzaro F, Sapountzi V, Granata M, et al. (2008). Histone methyltransferase Dot1 and Rad9 inhibit single-stranded DNA accumulation at DSBs and uncapped telomeres. EMBO J 27:1502–12.
  • Lee K, Lee SE. (2007). Saccharomyces cerevisiae Sae2- and Tel1-dependent single-strand DNA formation at DNA break promotes microhomology-mediated end joining. Genetics 176:2003–14.
  • Lee SE, Bressan DA, Petrini JH, Haber JE. (2002). Complementation between N-terminal Saccharomyces cerevisiae mre11 alleles in DNA repair and telomere length maintenance. DNA Repair (Amst) 1:27–40.
  • Lengsfeld BM, Rattray AJ, Bhaskara V, et al. (2007). Sae2 is an endonuclease that processes hairpin DNA cooperatively with the Mre11/Rad50/Xrs2 complex. Mol Cell 28:638–51.
  • Liang J, Suhandynata RT, Zhou H. (2015). Phosphorylation of Sae2 mediates forkhead-associated (FHA) domain-specific interaction and regulates its DNA repair function. J Biol Chem 290:10751–63.
  • Liao S, Toczylowski T, Yan H. (2008). Identification of the Xenopus DNA2 protein as a major nuclease for the 5′->3′ strand-specific processing of DNA ends. Nucleic Acids Res 36:6091–100.
  • Lim HS, Kim JS, Park YB, et al. (2011). Crystal structure of the Mre11–Rad50–ATPγS complex: understanding the interplay between Mre11 and Rad50 . Genes Dev 25:1091–104.
  • Limbo O, Chahwan C, Yamada Y, et al. (2007). Ctp1 is a cell-cycle-regulated protein that functions with Mre11 complex to control double-strand break repair by homologous recombination. Mol Cell 28:134–46.
  • Lisby M, Barlow JH, Burgess RC, Rothstein R. (2004). Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. Cell 118:699–713.
  • Llorente B, Symington LS. (2004). The Mre11 nuclease is not required for 5′ to 3′ resection at multiple HO-induced double-strand breaks. Mol Cell Biol 24:9682–94.
  • Lloyd J, Chapman JR, Clapperton JA, et al. (2009). A supramodular FHA/BRCT-repeat architecture mediates Nbs1 adaptor function in response to DNA damage. Cell 139:100–11.
  • Lobachev KS, Gordenin DA, Resnick MA. (2002). The Mre11 complex is required for repair of hairpin-capped double-strand breaks and prevention of chromosome rearrangements. Cell 108:183–93.
  • Luo G, Yao MS, Bender CF, et al. (1999). Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation. Proc Natl Acad Sci USA 96:7376–81.
  • Ma Y, Pannicke U, Schwarz K, Lieber MR. (2002). Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 108:781–94.
  • Makharashvili N, Tubbs AT, Yang SH, et al. (2014). Catalytic and noncatalytic roles of the CtIP endonuclease in double-strand break end resection. Mol Cell 54:1022–33.
  • Manfrini N, Guerini I, Citterio A, et al. (2010). Processing of meiotic DNA double strand breaks requires cyclin-dependent kinase and multiple nucleases. J Biol Chem 285:11628–37.
  • Mantiero D, Clerici M, Lucchini G, Longhese MP. (2007). Dual role for Saccharomyces cerevisiae Tel1 in the checkpoint response to double-strand breaks. EMBO Rep 8:380–7.
  • McKee AH, Kleckner N. (1997). A general method for identifying recessive diploid-specific mutations in Saccharomyces cerevisiae, its application to the isolation of mutants blocked at intermediate stages of meiotic prophase and characterization of a new gene SAE2. Genetics 146:797–816.
  • McKinnon PJ, Caldecott KW. (2007). DNA strand break repair and human genetic disease. Annu Rev Genom Hum Genet 8:37–55.
  • Mimitou EP, Symington LS. (2008). Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455:770–4.
  • Mimitou EP, Symington LS. (2009). DNA end resection: many nucleases make light work. DNA Repair (Amst) 8:983–95.
  • Mimitou EP, Symington LS. (2010). Ku prevents Exo1 and Sgs1-dependent resection of DNA ends in the absence of a functional MRX complex or Sae2. EMBO J 29:3358–69.
  • Modrich P. (2006). Mechanisms in eukaryotic mismatch repair. J Biol Chem 281:30305–9.
  • Moreau S, Ferguson JR, Symington LS. (1999). The nuclease activity of Mre11 is required for meiosis but not for mating type switching, end joining, or telomere maintenance. Mol Cell Biol 19:556–66.
  • Moreau S, Morgan EA, Symington LS. (2001). Overlapping functions of the Saccharomyces cerevisiae Mre11, Exo1 and Rad27 nucleases in DNA metabolism. Genetics 159:1423–33.
  • Morin I, Ngo HP, Greenall A, et al. (2008). Checkpoint-dependent phosphorylation of Exo1 modulates the DNA damage response. EMBO J 27:2400–10.
  • Murakami H, Keeney S. (2014). Temporospatial coordination of meiotic DNA replication and recombination via DDK recruitment to replisomes. Cell 158:861–73.
  • Myler LR, Gallardo IF, Zhou Y, et al. (2016). Single-molecule imaging reveals the mechanism of Exo1 regulation by single-stranded DNA binding proteins. Proc Natl Acad Sci USA 113:E1170–9.
  • Nakada D, Matsumoto K, Sugimoto K. (2003). ATM-related Tel1 associates with double-strand breaks through an Xrs2-dependent mechanism. Genes Dev 17:1957–62.
  • Nakamura K, Kogame T, Oshiumi H, et al. (2010). Collaborative action of Brca1 and CtIP in elimination of covalent modifications from double-strand breaks to facilitate subsequent break repair. PLoS Genet 6:e1000828.
  • Neale MJ, Pan J, Keeney S. (2005). Endonucleolytic processing of covalent protein-linked DNA double-strand breaks. Nature 436:1053–7.
  • Ngo GH, Balakrishnan L, Dubarry M, et al. (2014). The 9-1-1 checkpoint clamp stimulates DNA resection by Dna2–Sgs1 and Exo1. Nucleic Acids Res 42:10516–28.
  • Ngo GH, Lydall D. (2015). The 9-1-1 checkpoint clamp coordinates resection at DNA double strand breaks. Nucleic Acids Res 43:5017–32.
  • Ngo HP, Lydall D. (2010). Survival and growth of yeast without telomere capping by Cdc13 in the absence of Sgs1, Exo1, and Rad9. PLoS Genet 6:e1001072.
  • Nicolette ML, Lee K, Guo Z, et al. (2010). Mre11–Rad50–Xrs2 and Sae2 promote 5′ strand resection of DNA double-strand breaks. Nat Struct Mol Biol 17:1478–85.
  • Nimonkar AV, Genschel J, Kinoshita E, 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.
  • Nimonkar AV, Ozsoy AZ, Genschel J, et al. (2008). Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair. Proc Natl Acad Sci USA 105:16906–11.
  • Niu H, Chung WH, Zhu Z, et al. (2010). Mechanism of the ATP-dependent DNA end-resection machinery from Saccharomyces cerevisiae. Nature 467:108–11.
  • O'Driscoll M. (2012). Diseases associated with defective responses to DNA damage. Cold Spring Harbor Perspect Biol 4:a012773.
  • Orthwein A, Noordermeer SM, Wilson MD, et al. (2015). A mechanism for the suppression of homologous recombination in G1 cells. Nature 528:422–6.
  • Palmbos PL, Wu D, Daley JM, Wilson TE. (2008). Recruitment of Saccharomyces cerevisiae Dnl4–Lif1 complex to a double-strand break requires interactions with Yku80 and the Xrs2 FHA domain. Genetics 180:1809–19.
  • Paques F, Haber JE. (1999). Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 63:349–404.
  • Paull TT, Gellert M. (1998). The 3′ to 5′ exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks. Mol Cell 1:969–79.
  • Paull TT, Gellert M. (1999). Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex. Genes Dev 13:1276–88.
  • Peterson SE, Li Y, Wu-Baer F, et al. (2013). Activation of DSB processing requires phosphorylation of CtIP by ATR. Mol Cell 49:657–67.
  • Pierce AJ, Hu P, Han M, et al. (2001). Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev 15:3237–42.
  • Polato F, Callen E, Wong N, et al. (2014). CtIP-mediated resection is essential for viability and can operate independently of BRCA1. J Exp Med 211:1027–36.
  • Prinz S, Amon A, Klein F. (1997). Isolation of COM1, a new gene required to complete meiotic double-strand break-induced recombination in Saccharomyces cerevisiae. Genetics 146:781–95.
  • Puddu F, Oelschlaegel T, Guerini I, et al. (2015). Synthetic viability genomic screening defines Sae2 function in DNA repair. EMBO J 34:1509–22.
  • Rass E, Grabarz A, Plo I, et al. (2009). Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells. Nat Struct Mol Biol 16:819–24.
  • Rattray AJ, Shafer BK, Neelam B, Strathern JN. (2005). A mechanism of palindromic gene amplification in Saccharomyces cerevisiae. Genes Dev 19:1390–9.
  • Reczek CR, Szabolcs M, Stark JM, et al. (2013). The interaction between CtIP and BRCA1 is not essential for resection-mediated DNA repair or tumor suppression. J Cell Biol 201:693–707.
  • Roberts SA, Sterling J, Thompson C, et al. (2012). Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol Cell 46:424–35.
  • San Filippo J, Sung P, Klein H. (2008). Mechanism of eukaryotic homologous recombination. Annu Rev Biochem 77:229–57.
  • Sartori AA, Lukas C, Coates J, et al. (2007). Human CtIP promotes DNA end resection. Nature 450:509–14.
  • Schatz DG, Swanson PC. (2011). V(D)J recombination: mechanisms of initiation. Annu Rev Genet 45:167–202.
  • Schiller CB, Lammens K, Guerini I, et al. (2012). Structure of Mre11–Nbs1 complex yields insights into ataxia-telangiectasia-like disease mutations and DNA damage signaling. Nat Struct Mol Biol 19:693–700.
  • Sfeir A, de Lange T. (2012). Removal of shelterin reveals the telomere end-protection problem. Science 336:593–7.
  • Sfeir A, Symington LS. (2015). Microhomology-mediated end joining: a back-up survival mechanism or dedicated pathway? Trends Biochem Sci 40:701–14.
  • Shibata A, Moiani D, Arvai AS, et al. (2014). DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities. Mol Cell 53:7–18.
  • Shim EY, Chung WH, Nicolette ML, et al. (2010). Saccharomyces cerevisiae Mre11/Rad50/Xrs2 and Ku proteins regulate association of Exo1 and Dna2 with DNA breaks. EMBO J 29:3370–80.
  • Shim EY, Hong SJ, Oum JH, et al. (2007). RSC mobilizes nucleosomes to improve accessibility of repair machinery to the damaged chromatin. Mol Cell Biol 27:1602–13.
  • Shiotani B, Zou L. (2009). Single-stranded DNA orchestrates an ATM-to-ATR switch at DNA breaks. Mol Cell 33:547–58.
  • Stewart GS, Maser RS, Stankovic T, et al. (1999). The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99:577–87.
  • Stracker TH, Petrini JH. (2011). The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol 12:90–103.
  • Sturzenegger A, Burdova K, Kanagaraj R, et al. (2014). DNA2 cooperates with the WRN and BLM RecQ helicases to mediate long-range DNA end resection in human cells. J Biol Chem 289:27314–26.
  • Sun H, Treco D, Szostak JW. (1991). Extensive 3′-overhanging, single-stranded DNA associated with the meiosis-specific double-strand breaks at the ARG4 recombination initiation site. Cell 64:1155–61.
  • Symington LS, Gautier J. (2011). Double-strand break end resection and repair pathway choice. Annu Rev Genet 45:247–71.
  • Symington LS, Rothstein R, Lisby M. (2014). Mechanisms and regulation of mitotic recombination in Saccharomyces cerevisiae. Genetics 198:795–835.
  • Szankasi P, Smith GR. (1992). A DNA exonuclease induced during meiosis of Schizosaccharomyces pombe. J Biol Chem 267:3014–23.
  • Szankasi P, Smith GR. (1995). A role for exonuclease I from S. pombe in mutation avoidance and mismatch correction. Science 267:1166–9.
  • Thangavel S, Berti M, Levikova M, et al. (2015). DNA2 drives processing and restart of reversed replication forks in human cells. J Cell Biol 208:545–62.
  • Tishkoff DX, Amin NS, Viars CS, et al. (1998). Identification of a human gene encoding a homologue of Saccharomyces cerevisiae EXO1, an exonuclease implicated in mismatch repair and recombination. Cancer Res 58:5027–31.
  • Tkac J, Xu G, Adhikary H, et al. (2016). HELB is a feedback inhibitor of DNA end resection. Mol Cell 61:405–18.
  • Toczylowski T, Yan H. (2006). Mechanistic analysis of a DNA end processing pathway mediated by the Xenopus Werner syndrome protein. J Biol Chem 281:33198–205.
  • Tomimatsu N, Mukherjee B, Catherine Hardebeck M, et al. (2014). Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice. Nat Commun 5:3561.
  • Tomimatsu N, Mukherjee B, Deland K, et al. (2012). Exo1 plays a major role in DNA end resection in humans and influences double-strand break repair and damage signaling decisions. DNA Repair (Amst) 11:441–8.
  • Trovesi C, Falcettoni M, Lucchini G, et al. (2011). Distinct Cdk1 requirements during single-strand annealing, noncrossover, and crossover recombination. PLoS Genet 7:e1002263.
  • Trujillo KM, Sung P. (2001). DNA structure-specific nuclease activities in the Saccharomyces cerevisiae Rad50*Mre11 complex. J Biol Chem 276:35458–64.
  • Truong LN, Li Y, Shi LZ, et al. (2013). Microhomology-mediated end joining and homologous recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells. Proc Natl Acad Sci USA 110:7720–5.
  • Tsubouchi H, Ogawa H. (2000). Exo1 roles for repair of DNA double-strand breaks and meiotic crossing over in Saccharomyces cerevisiae. Mol Biol Cell 11:2221–33.
  • Tsukamoto Y, Mitsuoka C, Terasawa M, et al. (2005). Xrs2p regulates Mre11p translocation to the nucleus and plays a role in telomere elongation and meiotic recombination. Mol Biol Cell 16:597–608.
  • Usui T, Ogawa H, Petrini JH. (2001). A DNA damage response pathway controlled by Tel1 and the Mre11 complex. Mol Cell 7:1255–66.
  • Usui T, Ohta T, Oshiumi H, et al. (1998). Complex formation and functional versatility of Mre11 of budding yeast in recombination. Cell 95:705–16.
  • Villarreal DD, Lee K, Deem A, et al. (2012). Microhomology directs diverse DNA break repair pathways and chromosomal translocations. PLoS Genet 8:e1003026.
  • Waltes R, Kalb R, Gatei M, et al. (2009). Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder. Am J Hum Genet 84:605–16.
  • Wang H, Li Y, Truong LN, et al. (2014). CtIP maintains stability at common fragile sites and inverted repeats by end resection-independent endonuclease activity. Mol Cell 54:1012–21.
  • Wang H, Shao Z, Shi LZ, et al. (2012). CtIP protein dimerization is critical for its recruitment to chromosomal DNA double-stranded breaks. J Biol Chem 287:21471–80.
  • Wang H, Shi LZ, Wong CC, et al. (2013). The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair. PLoS Genet 9:e1003277.
  • Wang J, Aroumougame A, Lobrich M, et al. (2014). PTIP associates with Artemis to dictate DNA repair pathway choice. Genes Dev 28:2693–8.
  • Wang X, Haber JE. (2004). Role of Saccharomyces single-stranded DNA-binding protein RPA in the strand invasion step of double-strand break repair. PLoS Biol 2:E21.
  • West SC, Blanco MG, Chan YW, et al. (2015). Resolution of recombination intermediates: mechanisms and regulation. Cold Spring Harb Symp Quant Biol 80:027649.
  • Westmoreland JW, Resnick MA. (2016). Recombinational repair of radiation-induced double-strand breaks occurs in the absence of extensive resection. Nucleic Acids Res 44:695–704.
  • White CI, Haber JE. (1990). Intermediates of recombination during mating type switching in Saccharomyces cerevisiae. EMBO J 9:663–73.
  • Williams GJ, Williams RS, Williams JS, et al. (2011). ABC ATPase signature helices in Rad50 link nucleotide state to Mre11 interface for DNA repair. Nat Struct Mol Biol 18:423–31.
  • Williams RS, Dodson GE, Limbo O, et al. (2009). Nbs1 flexibly tethers Ctp1 and Mre11–Rad50 to coordinate DNA double-strand break processing and repair. Cell 139:87–99.
  • Williams RS, Moncalian G, Williams JS, et al. (2008). Mre11 dimers coordinate DNA end bridging and nuclease processing in double-strand-break repair. Cell 135:97–109.
  • Wiltshire TD, Lovejoy CA, Wang T, et al. (2010). Sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition identifies ubiquitin-specific peptidase 11 (USP11) as a regulator of DNA double-strand break repair. J Biol Chem 285:14565–71.
  • Xiao Y, Weaver DT. (1997). Conditional gene targeted deletion by Cre recombinase demonstrates the requirement for the double-strand break repair Mre11 protein in murine embryonic stem cells. Nucleic Acids Res 25:2985–91.
  • Xie A, Kwok A, Scully R. (2009). Role of mammalian Mre11 in classical and alternative nonhomologous end joining. Nat Struct Mol Biol 16:814–8.
  • Xu G, Chapman JR, Brandsma I, et al. (2015). REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature 521:541–4.
  • Yan H, Toczylowski T, McCane J, et al. (2011). Replication protein A promotes 5′->3′ end processing during homology-dependent DNA double-strand break repair. J Cell Biol 192:251–61.
  • Yang SH, Zhou R, Campbell J, et al. (2013). The SOSS1 single-stranded DNA binding complex promotes DNA end resection in concert with Exo1. EMBO J 32:126–39.
  • You Z, Chahwan C, Bailis J, et al. (2005). ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1. Mol Cell Biol 25:5363–79.
  • You Z, Shi LZ, Zhu Q, et al. (2009). CtIP links DNA double-strand break sensing to resection. Mol Cell 36:954–69.
  • Zakharyevich K, Ma Y, Tang S, et al. (2010). Temporally and biochemically distinct activities of Exo1 during meiosis: double-strand break resection and resolution of double Holliday junctions. Mol Cell 40:1001–15.
  • Zhou Y, Caron P, Legube G, Paull TT. (2014). Quantitation of DNA double-strand break resection intermediates in human cells. Nucleic Acids Res 42:e19.
  • Zhu J, Petersen S, Tessarollo L, Nussenzweig A. (2001). Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Curr Biol 11:105–9.
  • Zhu Z, Chung WH, Shim EY, et al. (2008). Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134:981–94.
  • Zierhut C, Diffley JF. (2008). Break dosage, cell cycle stage and DNA replication influence DNA double strand break response. EMBO J 27:1875–85.
  • Zimmermann M, de Lange T. (2014). 53BP1: pro choice in DNA repair. Trends Cell Biol 24:108–17.
  • Zimmermann M, Lottersberger F, Buonomo SB, et al. (2013). 53BP1 regulates DSB repair using Rif1 to control 5′ end resection. Science 339:700–4.
  • Zou L, Elledge SJ. (2003). Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300:1542–8.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.