Skip to main content
SpringerLink
Log in

Nonhomologous end-joining: mechanisms, conservation and relationship to illegitimate recombination

  • Chapter
Molecular Genetics of Recombination

Part of the book series: Topics in Current Genetics ((TCG,volume 17))

Abstract

Illegitimate recombination (IR) is the exchange of genetic information by formation of junctions between nonhomologous chromosome segments. IR is intimately associated with the process of nonhomologous end-joining (NHEJ) that is dependent on Ku, DNA ligase IV, and associated proteins. Other processes also appear to be at play at in IR which have varying degrees of overlap with NHEJ, homologous recombination and single-strand break repair, and which depend on structural features of the initiating double-strand breaks (DSBs). This review takes a broad view of these issues by considering the conservation of Ku-dependent NHEJ and related processes from bacteria to man. Both extensive conservation and marked variability are evident, providing a rich future framework for correlating life cycles, DSB rejoining mechanisms, repair accuracy, and other selectable evolutionary benefits of NHEJ.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Ahnesorg P, Smith P, Jackson SP (2006) XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124:301–313

    CAS  PubMed  Google Scholar 

  • Akey D, Martins A, Aniukwu J, Glickman MS, Shuman S, Berger JM (2006) Crystal structure and nonhomologous end joining function of the ligase component of Mycobacte-rium DNA ligase D. J Biol Chem 281:13412–13423

    CAS  PubMed  Google Scholar 

  • Aravind L, Koonin EV (2001) Prokaryotic homologs of the eukaryotic DNA-end-binding protein Ku, novel domains in the Ku protein and prediction of a prokaryotic double-strand break repair system. Genome Res 11:1365–1374

    CAS  PubMed Central  PubMed  Google Scholar 

  • Audebert M, Salles B, Calsou P (2004) Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J Biol Chem 279:55117–55126

    CAS  PubMed  Google Scholar 

  • Audebert M, Salles B, Weinfeld M, Calsou P (2006) Involvement of polynucleotide kinase in a poly(ADP-ribose) polymerase-1-dependent DNA double-strand breaks rejoining pathway. J Mol Biol 356:257–265

    CAS  PubMed  Google Scholar 

  • Bebenek K, Garcia-Diaz M, Blanco L, Kunkel TA (2003) The frameshift infidelity of human DNA polymerase lambda. Implications for function. J Biol Chem 278:34685–34690

    CAS  PubMed  Google Scholar 

  • Block WD, Lees-Miller SP (2005) Putative homologues of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and other components of the non-homologous end joining machinery in Dictyostelium discoideum. DNA Repair 4:1061–1065

    CAS  PubMed  Google Scholar 

  • Bonatto D, Brendel M, Henriques JA (2005) In silico identification and analysis of new Artemis/Artemis-like sequences from fungal and metazoan species. Protein J 24:399–411

    CAS  PubMed  Google Scholar 

  • Boulton SJ, Jackson SP (1996) Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways. EMBO J 15:5093–5103

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bryans M, Valenzano MC, Stamato TD (1999) Absence of DNA ligase IV protein in XR-1 cells: evidence for stabilization by XRCC4. Mutat Res 433:53–58

    CAS  PubMed  Google Scholar 

  • Buck D, Malivert L, de Chasseval R, Barraud A, Fondaneche MC, Sanal O, Plebani A, Stephan JL, Hufnagel M, le Deist F, Fischer A, Durandy A, de Villartay JP, Revy P (2006) Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124:287–299

    CAS  PubMed  Google Scholar 

  • Budman J, Chu G (2005) Processing of DNA for nonhomologous end-joining by cell-free extract. EMBO J 24:849–860

    CAS  PubMed Central  PubMed  Google Scholar 

  • Callebaut I, Moshous D, Mornon JP, de Villartay JP (2002) Metallo-beta-lactamase fold within nucleic acids processing enzymes: the beta-CASP family. Nucleic Acids Res 30:3592–3601

    CAS  PubMed Central  PubMed  Google Scholar 

  • Callebaut I, Malivert L, Fischer A, Mornon JP, Revy P, de Villartay JP (2006) Cernunnos interacts with the XRCC4 x DNA-ligase IV complex and is homologous to the yeast nonhomologous end-joining factor Nej1. J Biol Chem 281:13857–13860

    CAS  PubMed  Google Scholar 

  • Capp JP, Boudsocq F, Bertrand P, Laroche-Clary A, Pourquier P, Lopez BS, Cazaux C, Hoffmann JS, Canitrot Y (2006) The DNA polymerase lambda is required for the re-pair of non-compatible DNA double strand breaks by NHEJ in mammalian cells. Nu-cleic Acids Res 34:2998–3007

    CAS  Google Scholar 

  • Chappell C, Hanakahi LA, Karimi-Busheri F, Weinfeld M, West SC (2002) Involvement of human polynucleotide kinase in double-strand break repair by non-homologous end joining. EMBO J 21:2827–2832

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chen L, Trujillo K, Ramos W, Sung P, Tomkinson AE (2001) Promotion of Dnl4-catalyzed DNA end-joining by the Rad50/Mre11/Xrs2 and Hdf1/Hdf2 complexes. Mol Cell 8:1105–1115

    CAS  PubMed  Google Scholar 

  • Clejan I, Boerckel J, Ahmed S (2006) Developmental modulation of nonhomologous end joining in Caenorhabditis elegans. Genetics 173:1301–1317

    CAS  PubMed Central  PubMed  Google Scholar 

  • Connelly JC, Leach DR (2002) Tethering on the brink: the evolutionarily conserved Mre11 Rad50 complex. Trends Biochem Sci 27:410–418

    CAS  PubMed  Google Scholar 

  • Covo S, Blanco L, Livneh Z (2004) Lesion bypass by human DNA polymerase mu reveals a template-dependent, sequence-independent nucleotidyl transferase activity. J Biol Chem 279:859–865

    CAS  PubMed  Google Scholar 

  • Daley JM, Laan RL, Suresh A, Wilson TE (2005) DNA joint dependence of pol X family polymerase action in nonhomologous end joining. J Biol Chem 280:29030–29037

    CAS  PubMed  Google Scholar 

  • Daley JM, Palmbos PL, Wu D, Wilson TE (2005) Nonhomologous end joining in yeast. Annu Rev Genet 39:431–451

    CAS  PubMed  Google Scholar 

  • Daley JM, Wilson TE (2005) Rejoining of DNA double-strand breaks as a function of overhang length. Mol Cell Biol 25:896–906

    CAS  PubMed Central  PubMed  Google Scholar 

  • Daniel R, Greger JG, Katz RA, Taganov KD, Wu X, Kappes JC, Skalka AM (2004) Evidence that stable retroviral transduction and cell survival following DNA integration depend on components of the nonhomologous end joining repair pathway. J Virol 78:8573–8581

    CAS  PubMed Central  PubMed  Google Scholar 

  • de la Torre-Ruiz M, Lowndes NF (2000) The Saccharomyces cerevisiae DNA damage checkpoint is required for efficient repair of double strand breaks by non-homologous end joining. FEBS Lett 467:311–315

    PubMed  Google Scholar 

  • Decottignies A (2005) Capture of extranuclear DNA at fission yeast double-strand breaks. Genetics 171:1535–1548

    CAS  PubMed Central  PubMed  Google Scholar 

  • DeFazio LG, Stansel RM, Griffith JD, Chu G (2002) Synapsis of DNA ends by DNA-dependent protein kinase. EMBO J 21:3192–3200

    CAS  PubMed Central  PubMed  Google Scholar 

  • Della M, Palmbos PL, Tseng HM, Tonkin LM, Daley JM, Topper LM, Pitcher RS, Tomkinson AE, Wilson TE, Doherty AJ (2004) Mycobacterial Ku and ligase proteins con-stitute a twocomponent NHEJ repair machine. Science 306:683–685

    CAS  PubMed  Google Scholar 

  • Di Virgilio M, Gautier J (2005) Repair of double-strand breaks by nonhomologous end joining in the absence of Mre11. J Cell Biol 171:765–771

    Google Scholar 

  • Doherty AJ, Jackson SP, Weller GR (2001) Identification of bacterial homologues of the Ku DNA repair proteins. FEBS Lett 500:186–188

    CAS  PubMed  Google Scholar 

  • Dore AS, Drake AC, Brewerton SC, Blundell TL (2004) Identification of DNA-PK in the arthropods. Evidence for the ancient ancestry of vertebrate non-homologous end-joining. DNA Repair (Amst) 3:33–41

    CAS  Google Scholar 

  • Downs JA, Jackson SP (1999) Involvement of DNA end-binding protein Ku in Ty element retrotransposition. Mol Cell Biol 19:6260–6268

    CAS  PubMed Central  PubMed  Google Scholar 

  • Drouet J, Frit P, Delteil C, de Villartay JP, Salles B, Calsou P (2006) Interplay between Ku, artemis and DNA-PKcs at DNA ends. J Biol Chem: in press

    Google Scholar 

  • Ferreira MG, Cooper JP (2004) Two modes of DNA double-strand break repair are recipro-cally regulated through the fission yeast cell cycle. Genes Dev 18:2249–2254

    CAS  PubMed Central  PubMed  Google Scholar 

  • Frank KM, Sharpless NE, Gao Y, Sekiguchi JM, Ferguson DO, Zhu C, Manis JP, Horner J, DePinho RA, Alt FW (2000) DNA ligase IV deficiency in mice leads to defective neu-rogenesis and embryonic lethality via the p53 pathway. Mol Cell 5:993–1002

    CAS  PubMed  Google Scholar 

  • Frank-Vaillant M, Marcand S (2001) NHEJ regulation by mating type is exercised through a novel protein, Lif2p, essential to the ligase IV pathway. Genes Dev 15:3005–3012

    CAS  PubMed Central  PubMed  Google Scholar 

  • Friedberg EC, Walker GC, Siede W, Wood RD, Schultz RA, Ellenberger T (2005) DNA repair and mutagenesis. ASM Press, Washington DC

    Google Scholar 

  • Friesner J, Britt AB (2003) Ku80-and DNA ligase IV-deficient plants are sensitive to ion-izing radiation and defective in T-DNA integration. Plant J 34:427–440

    CAS  PubMed  Google Scholar 

  • Gallego ME, Bleuyard JY, Daoudal-Cotterell S, Jallut N, White CI (2003) Ku80 plays a role in non-homologous recombination but is not required for T-DNA integration in Arabidopsis. Plant J 35:557–565

    CAS  PubMed  Google Scholar 

  • Garcia-Diaz M, Bebenek K, Krahn JM, Pedersen LC, Kunkel TA (2006) Structural analysis of strand misalignment during DNA synthesis by a human DNA polymerase. Cell 124:331–342

    CAS  PubMed  Google Scholar 

  • Garcia-Diaz M, Bebenek K, Kunkel TA, Blanco L (2001) Identification of an intrinsic 5’-deoxyribose-5-phosphate lyase activity in human DNA polymerase lambda: a possible role in base excision repair. J Biol Chem 276:34659–34663

    CAS  PubMed  Google Scholar 

  • Gell D, Jackson SP (1999) Mapping of protein-protein interactions within the DNA-dependent protein kinase complex. Nucleic Acids Res 27:3494–3502

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gong C, Bongiorno P, Martins A, Stephanou NC, Zhu H, Shuman S, Glickman MS (2005) Mechanism of nonhomologous end-joining in mycobacteria: a low-fidelity repair sys-tem driven by Ku, ligase D and ligase C. Nat Struct Mol Biol 12:304–312

    CAS  PubMed  Google Scholar 

  • Gonzalez-Barrera S, Sanchez A, Ruiz JF, Juarez R, Picher AJ, Terrados G, Andrade P, Blanco L (2005) Characterization of SpPol4, a unique X-family DNA polymerase in Schizosaccharomyces pombe. Nucleic Acids Res 33:4762–4774

    CAS  PubMed Central  PubMed  Google Scholar 

  • Goodarzi AA, Yu Y, Riballo E, Douglas P, Walker SA, Ye R, Harer C, Marchetti C, Mor-rice N, Jeggo PA, Lees-Miller SP (2006) DNA-PK autophosphorylation facilitates Ar-temis endonuclease activity. EMBO J: in press

    Google Scholar 

  • Gottlieb TM, Jackson SP (1993) The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell 72:131–142

    CAS  PubMed  Google Scholar 

  • Grawunder U, Wilm M, Wu X, Kulesza P, Wilson TE, Mann M, Lieber MR (1997) Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature 388:492–495

    CAS  PubMed  Google Scholar 

  • Haber JE (1999) DNA recombination: the replication connection. Trends Biochem Sci 24:271–275

    CAS  PubMed  Google Scholar 

  • Hammarsten O, DeFazio LG, Chu G (2000) Activation of DNA-dependent protein kinase by single-stranded DNA ends. J Biol Chem 275:1541–1550

    CAS  PubMed  Google Scholar 

  • Kellis M, Birren BW, Lander ES (2004) Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiae. Nature 428:617–624

    CAS  PubMed  Google Scholar 

  • Heidenreich E, Eisler H (2004) Non-homologous end joining dependency of gamma-irradiation-induced adaptive frameshift mutation formation in cell cycle-arrested yeast cells. Mutat Res 556:201–208

    CAS  PubMed  Google Scholar 

  • Hochegger H, Dejsuphong D, Fukushima T, Morrison C, Sonoda E, Schreiber V, Zhao GY, Saberi A, Masutani M, Adachi N, Koyama H, de Murcia G, Takeda S (2006) Parp-1 protects homologous recombination from interference by Ku and ligase IV in verte-brate cells. EMBO J 25:1305–1314

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hope JC, Mense SM, Jalakas M, Mitsumoto J, Freyer GA (2006) Rqh1 blocks recombina-tion between sister chromatids during double strand break repair, independent of its helicase activity. Proc Natl Acad Sci USA 103:5875–5880

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huang J, Dynan WS (2002) Reconstitution of the mammalian DNA double-strand break end-joining reaction reveals a requirement for an Mre11/Rad50/NBS1-containing frac-tion. Nucleic Acids Res 30:667–674

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hudson JJ, Hsu DW, Guo K, Zhukovskaya N, Liu PH, Williams JG, Pears CJ, Lakin ND (2005) DNA-PKcs-Dependent Signaling of DNA Damage in Dictyostelium discoideum. Curr Biol 15:1880–1885

    CAS  PubMed  Google Scholar 

  • Ira G, Pellicioli A, Balijja A, Wang X, Fiorani S, Carotenuto W, Liberi G, Bressan D, Wan L, Hollingsworth NM, Haber JE, Foiani M (2004) DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431:1011–1017

    CAS  PubMed  Google Scholar 

  • Ivanov EL, Haber JE (1995) RAD1 and RAD10, but not other excision repair genes, are required for double-strand break-induced recombination in Saccharomyces cerevisiae. Mol Cell Biol 15:2245–2251

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jung D, Giallourakis C, Mostoslavsky R, Alt FW (2006) Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev Immunol 24:541–570

    CAS  PubMed  Google Scholar 

  • Kabotyanski EB, Gomelsky L, Han JO, Stamato TD, Roth DB (1998) Double-strand break repair in Ku86-and XRCC4-deficient cells. Nucleic Acids Res 26:5333–5342

    CAS  PubMed Central  PubMed  Google Scholar 

  • Karathanasis E, Wilson TE (2002) Enhancement of Saccharomyces cerevisiae end-joining efficiency by cell growth stage but not by impairment of recombination. Genetics 161:1015–1027

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kegel A, Martinez P, Carter SD, Astrom SU (2006) Genome wide distribution of illegitimate recombination events in Kluyveromyces lactis. Nucleic Acids Res 34:1633–1645

    CAS  PubMed Central  PubMed  Google Scholar 

  • Koch CA, Agyei R, Galicia S, Metalnikov P, O’Donnell P, Starostine A, Weinfeld M, Durocher D (2004) XRCC4 physically links DNA end processing by polynucleotide kinase to DNA ligation by DNA ligase IV. EMBO J 23:3874–3885

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kooistra R, Hooykaas PJ, Steensma HY (2004) Efficient gene targeting in Kluyveromyces lactis. Yeast 21:781–792

    CAS  PubMed  Google Scholar 

  • Krappmann S, Sasse C, Braus GH (2006) Gene targeting in Aspergillus fumigatus by homologous recombination is facilitated in a nonhomologous end-joining-deficient genetic background. Eukaryot Cell 5:212–215

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kysela B, Doherty AJ, Chovanec M, Stiff T, Ameer-Beg SM, Vojnovic B, Girard PM, Jeggo PA (2003) Ku stimulation of DNA ligase IV-dependent ligation requires inward movement along the DNA molecule. J Biol Chem 278:22466–22474

    CAS  PubMed  Google Scholar 

  • Li L, Olvera JM, Yoder KE, Mitchell RS, Butler SL, Lieber M, Martin SL, Bushman FD (2001) Role of the non-homologous DNA end joining pathway in the early steps of retroviral infection. EMBO J 20:3272–3281

    CAS  PubMed Central  PubMed  Google Scholar 

  • Li Z, Otevrel T, Gao Y, Cheng HL, Seed B, Stamato TD, Taccioli GE, Alt FW (1995) The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination. Cell 83:1079–1089

    CAS  PubMed  Google Scholar 

  • Ma JL, Kim EM, Haber JE, Lee SE (2003) Yeast Mre11 and Rad1 proteins define a Kuindependent mechanism to repair double-strand breaks lacking overlapping end se-quences. Mol Cell Biol 23:8820–8828

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ma Y, Lu H, Tippin B, Goodman MF, Shimazaki N, Koiwai O, Hsieh CL, Schwarz K, Lieber MR (2004) A biochemically defined system for mammalian nonhomologous DNA end joining Mol Cell 16:701–713

    CAS  PubMed  Google Scholar 

  • 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 108:781–794

    CAS  PubMed  Google Scholar 

  • Mahajan KN, Nick McElhinny SA, Mitchell BS, RamsdenA DA (2002) Association of DNA polymerase µ with Ku and ligase IV: Role for pol µ in rnd-joining double-strand break repair Mol Cell Biol 22:5194–5202

    CAS  PubMed Central  PubMed  Google Scholar 

  • Manolis KG, Nimmo ER, Hartsuiker E, Carr AM, Jeggo PA, Allshire RC (2001) Novel functional requirements for non-homologous DNA end joining in Schizosaccharomy-ces pombe. EMBO J 20:210–221

    CAS  PubMed Central  PubMed  Google Scholar 

  • McVey M, Radut D, Sekelsky JJ (2004) End-joining repair of double-strand breaks in Drosophila melanogaster is largely DNA ligase IV independent. Genetics 168:2067–2076

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mimori T, Hardin JA (1986) Mechanism of interaction between Ku protein and DNA. J Biol Chem 261:10375–10379

    CAS  PubMed  Google Scholar 

  • Min B, Weinert BT, Rio DC (2004) Interplay between Drosophila Bloom’s syndrome helicase and Ku autoantigen during nonhomologous end joining repair of P elementinduced DNA breaks. Proc Natl Acad Sci USA 101:8906–8911

    CAS  PubMed Central  PubMed  Google Scholar 

  • Modesti M, Hesse JE, Gellert M (1999) DNA binding of XRCC4 protein is associated with V(D)J recombination but not with stimulation of DNA ligase IV activity. EMBO J 18:2008–2018

    CAS  PubMed Central  PubMed  Google Scholar 

  • Modesti M, Junop MS, Ghirlando R, van de Rakt M, Gellert M, Yang W, Kanaar R (2003) Tetramerization and DNA ligase IV interaction of the DNA double-strand break repair protein XRCC4 are mutually exclusive. J Mol Biol 334:215–228

    CAS  PubMed  Google Scholar 

  • Moshous D, Callebaut I, de Chasseval R, Corneo B, Cavazzana-Calvo M, Le Deist F, Tezcan I, Sanal O, Bertrand Y, Philippe N, Fischer A, de Villartay J (2001) Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105:177–186

    CAS  PubMed  Google Scholar 

  • Nick McElhinny SA, Havener JM, Garcia-Diaz M, Juarez R, Bebenek K, Kee BL, Blanco L, Kunkel TA, Ramsden DA (2005) A gradient of template dependence defines dis-tinct biological roles for family X polymerases in nonhomologous end joining. Mol Cell 19:357–366

    Google Scholar 

  • O’Driscoll M, Gennery AR, Seidel J, Concannon P, Jeggo PA (2004) An overview of three new disorders associated with genetic instability: LIG4 syndrome, RS-SCID and ATR-Seckel syndrome. DNA Repair 3:1227–1235

    CAS  Google Scholar 

  • Ooi SL, Shoemaker DD, Boeke JD (2001) A DNA microarray-based genetic screen for nonhomologous end-joining mutants in Saccharomyces cerevisiae. Science 294:2552–2556

    CAS  PubMed  Google Scholar 

  • Orii KE, Lee Y, Kondo N, McKinnon PJ (2006) Selective utilization of nonhomologous end-joining and homologous recombination DNA repair pathways during nervous sys-tem development. Proc Natl Acad Sci USA 103:10017–10022

    CAS  PubMed Central  PubMed  Google Scholar 

  • Palmbos PL, Daley JM, Wilson TE (2005) Mutations of the Yku80 C terminus and Xrs2 FHA domain specifically block yeast nonhomologous end joining. Mol Cell Biol 25:10782–10790

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pardo B, Ma E, Marcand S (2006) Mismatch tolerance by DNA polymerase Pol4 in the course of nonhomologous end joining in Saccharomyces cerevisiae. Genetics 172:2689–2694

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pascal JM, O’Brien PJ, Tomkinson AE, Ellenberger T (2004) Human DNA ligase I completely encircles and partially unwinds nicked DNA. Nature 432:473–478

    CAS  PubMed  Google Scholar 

  • Perrault R, Wang H, Wang M, Rosidi B, Iliakis G (2004) Backup pathways of NHEJ are suppressed by DNA-PK. J Cell Biochem 92:781–794

    CAS  PubMed  Google Scholar 

  • Peterson SR, Kurimasa A, Oshimura M, Dynan WS, Bradbury EM, Chen DJ (1995) Loss of the catalytic subunit of the DNA-dependent protein kinase in DNA double-strand-break-repair mutant mammalian cells. Proc Natl Acad Sci USA 92:3171–3174

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pfeiffer P, Thode S, Hancke J, Vielmetter W (1994) Mechanisms of overlap formation in nonhomologous DNA end joining. Mol Cell Biol 14:888–895

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pitcher RS, Tonkin LM, Daley JM, Palmbos PL, Green AJ, Velting TL, Brzostek A, Korycka-Machala M, Cresawn SC, Dziadek J, Hatfull GF, Wilson TE, Doherty AJ (2006) Mycobacteriophage exploit prokaryotic NHEJ to facilitate genome circularization. Mol Cell: in press

    Google Scholar 

  • Reddy YV, Ding Q, Lees-Miller SP, Meek K, Ramsden DA (2004) Non-homologous end joining requires that the DNA-PK complex undergo an autophosphorylation-dependent rearrangement at DNA ends J Biol Chem 279:39408–39413

    CAS  PubMed  Google Scholar 

  • Riballo E, Kuhne M, Rief N, Doherty A, Smith GC, Recio MJ, Reis C, Dahm K, Fricke A, Krempler A, Parker AR, Jackson SP, Gennery A, Jeggo PA, Lobrich M (2004) A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Mol Cell 16:715–724

    CAS  PubMed  Google Scholar 

  • Rivera-Calzada A, Maman JP, Spagnolo L, Pearl LH, Llorca O (2005) Three-dimensional structure and regulation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Structure (Camb) 13:243–255

    CAS  Google Scholar 

  • Romeijn RJ, Gorski MM, van Schie MA, Noordermeer JN, Mullenders LH, Ferro W, Pastink A (2005) Lig4 and Rad54 are required for repair of DNA double-strand breaks induced by p-element excision in Drosophila. Genetics 169:795–806

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sandoval A, Labhart P (2004) High G/C content of cohesive overhangs renders DNA end joining Ku-independent. DNA Repair 3:13–21

    CAS  PubMed  Google Scholar 

  • Sibanda BL, Critchlow SE, Begun J, Pei XY, Jackson SP, Blundell TL, Pellegrini L (2001) Crystal structure of an XRCC4-DNA ligase IV complex. Nat Struct Biol 8:1015–1019

    CAS  PubMed  Google Scholar 

  • Skalka AM, Katz RA (2005) Retroviral DNA integration and the DNA damage response. Cell Death Differ 12:971–978

    CAS  PubMed  Google Scholar 

  • Strang BL, Stow ND (2005) Circularization of the herpes simplex virus type 1 genome upon lytic infection. J Virol 79:12487–12494

    CAS  PubMed Central  PubMed  Google Scholar 

  • Spagnolo L, Rivera-Caldeza A, Pearl LH, Llorca O (2006) Three dimensional structure of the human DNA-PK/Ku70/Ku80 complex assembled on DNA and its implications for DNA DSB repair. Mol Cell 22:511–519

    CAS  PubMed  Google Scholar 

  • Sugawara N, Ira G, Haber JE (2000) DNA length dependence of the single-strand annealing pathway and the role of Saccharomyces cerevisiae RAD59 in double-strand break re-pair. Mol Cell Biol 20:5300–5309

    CAS  PubMed Central  PubMed  Google Scholar 

  • Taccioli GE, Gottlieb TM, Blunt T, Priestley A, Demengeot J, Mizuta R, Lehmann AR, Alt FW, Jackson SP, Jeggo PA (1994) Ku80: product of the XRCC5 gene and its role in DNA repair and V(D)J recombination. Science 265:1442–1445

    CAS  PubMed  Google Scholar 

  • Takata M, Sasaki MS, Sonoda E, Morrison C, Hashimoto M, Utsumi H, Yamaguchi-Iwai Y, Shinohara A, Takeda S (1998) Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J 17:5497–5508

    CAS  PubMed Central  PubMed  Google Scholar 

  • Teo SH, Jackson SP (2000) Lif1p targets the DNA ligase Lig4p to sites of DNA doublestrand breaks. Curr Biol 10:165–168

    CAS  PubMed  Google Scholar 

  • Tseng HM, Tomkinson AE (2004) Processing and joining of DNA ends coordinated by interactions among Dnl4/Lif1, Pol4, and FEN-1. J Biol Chem 279:47580–47588

    CAS  PubMed  Google Scholar 

  • Tsukuda T, Fleming AB, Nickoloff JA, Osley MA (2005) Chromatin remodelling at a DNA double-strand break site in Saccharomyces cerevisiae. Nature 438:379–383

    CAS  PubMed Central  PubMed  Google Scholar 

  • van Attikum H, Gasser SM (2005) ATP-dependent chromatin remodeling and DNA double-strand break repair. Cell Cycle 4:1011–1014

    PubMed  Google Scholar 

  • van Heemst D, Brugmans L, Verkaik NS, van Gent DC (2004) End-joining of blunt DNA double-strand breaks in mammalian fibroblasts is precise and requires DNA-PK and XRCC4. DNA Repair 3:43–50

    PubMed  Google Scholar 

  • Verkaik NS, Esveldt-van Lange RE, van Heemst D, Bruggenwirth HT, Hoeijmakers JH, Zdzienicka MZ, van Gent DC (2002) Different types of V(D)J recombination and end-joining defects in DNA double-strand break repair mutant mammalian cells. Eur J Immunol 32:701–709

    CAS  PubMed  Google Scholar 

  • Walker JR, Corpina RA, Goldberg J (2001) Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412:607–614

    CAS  PubMed  Google Scholar 

  • Wang H, Rosidi B, Perrault R, Wang M, Zhang L, Windhofer F, Iliakis G (2005) DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. Cancer Res 65:4020–4030

    CAS  PubMed  Google Scholar 

  • Weller GR, Doherty AJ (2001) A family of DNA repair ligases in bacteria? FEBS Lett 505:340–342

    CAS  PubMed  Google Scholar 

  • Weller GR, Kysela B, Roy R, Tonkin LM, Scanlan E, Della M, Devine SK, Day JP, Wilkinson A, di Fagagna F, Devine KM, Bowater RP, Jeggo PA, Jackson SP, Doherty AJ (2002) Identification of a DNA nonhomologous end-joining complex in bacteria. Science 297:1686–1689

    CAS  PubMed  Google Scholar 

  • West CE, Waterworth WM, Story GW, Sunderland PA, Jiang Q, Bray CM (2002) Disruption of the Arabidopsis AtKu80 gene demonstrates an essential role for AtKu80 protein in efficient repair of DNA double-strand breaks in vivo. Plant J 31:517–528

    CAS  PubMed  Google Scholar 

  • Wilson S, Warr N, Taylor DL, Watts FZ (1999) The role of Schizosaccharomyces pombe Rad32, the Mre11 homologue, and other DNA damage response proteins in non-homologous end joining and telomere length maintenance. Nucleic Acids Res 27:2655–2661

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wilson TE (2002) A genomics-based screen for yeast mutants with an altered recombination/end-joining repair ratio. Genetics 162:677–688

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wilson TE, Grawunder U, Lieber MR (1997) Yeast DNA ligase IV mediates non-homologous DNA end joining. Nature 388:495–498

    CAS  PubMed  Google Scholar 

  • Wilson TE, Lieber MR (1999) Efficient processing of DNA ends during yeast nonhomolo-gous end joining. Evidence for a DNA polymerase ß (Pol4)-dependent pathway. J Biol Chem 274:23599–23609

    CAS  PubMed  Google Scholar 

  • Wilson TE, Topper LM, Palmbos PL (2003) Non-homologous end-joining: bacteria join the chromosome breakdance. Trends Biochem Sci 28:62–66

    CAS  PubMed  Google Scholar 

  • Wu X, Wilson TE, Lieber MR (1999) A role for FEN-1 in nonhomologous DNA end join-ing: the order of strand annealing and nucleolytic processing events. Proc Natl Acad Sci USA 96:1303–1308

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yakovleva L, Shuman S (2006) Nucleotide misincorporation, 3’-mismatch extension, and responses to abasic sites and DNA adducts by the polymerase component of bacterial DNA ligase D. J Biol Chem 281:25026–25040

    CAS  PubMed  Google Scholar 

  • Yu Y, Wang W, Ding Q, Ye R, Chen D, Merkle D, Schriemer D, Meek K, Lees-Miller SP (2003) DNA-PK phosphorylation sites in XRCC4 are not required for survival after radiation or for V(D)J recombination. DNA Rep 2:1239–1252

    CAS  Google Scholar 

  • Zhu C, Mills KD, Ferguson DO, Lee C, Manis J, Fleming J, Gao Y, Morton CC, Alt FW (2002) Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplifi-cation subsequent to translocations. Cell 109:811–821

    CAS  PubMed  Google Scholar 

  • Zhu H, Nandakumar J, Aniukwu J, Wang LK, Glickman MS, Lima CD, Shuman S (2006) Atomic structure and nonhomologous end-joining function of the polymerase compo-nent of bacterial DNA ligase D. Proc Natl Acad Sci USA 103:1711–1716

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhu H, Shuman S (2005) Novel 3’-ribonuclease and 3’-phosphatase activities of the bacte-rial non-homologous end-joining protein, DNA ligase D. J Biol Chem 280:25973–25981

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University of Michigan Medical School, Ann Arbor MI, Rm. 2065 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA

    Thomas E. Wilson

Authors
  1. Thomas E. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Centro Andaluz de Biologia Molecular y Medicina Regenerativa CABIMER, CSIC-Universidad de Sevilla, Av. Américo Vespucio s/n, 41092, Sevilla, Spain

    Andrés Aguilera

  2. Department of Genetics & Development, Columbia University Medical Center, 701 West 168th Street, HHSC 1608, New York, NY, 10032-2704, USA

    Rodney Rothstein

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Wilson, T.E. (2007). Nonhomologous end-joining: mechanisms, conservation and relationship to illegitimate recombination. In: Aguilera, A., Rothstein, R. (eds) Molecular Genetics of Recombination. Topics in Current Genetics, vol 17. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-71021-9_17

Download citation

Publish with us

Policies and ethics

Search

Navigation