Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Single-strand break repair and genetic disease

Key Points

  • Single-strand breaks (SSBs) are the most common lesions arising in cells, and chromosomal single-strand break repair (SSBR) is a rapid and efficient process.

  • In addition to the rapid 'global' SSBR processes that remove SSBs throughout the genome and throughout interphase, there might be S-phase specific processes that operate at replication forks in conjunction with homologous recombination.

  • Two of the proteins that repair damaged DNA termini during global SSBR (tyrosyl-DNA phosphodiesterase 1 and aprataxin) are mutated in the hereditary genetic diseases spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) and ataxia oculomotor apraxia 1 (AOA1), implicating unrepaired SSBs in progressive neurological dysfunction.

  • Whereas post-mitotic cells seem to be dependent on global SSBR for genetic integrity, proliferating cells can additionally use replication-coupled SSBR. This might explain why SCAN1 and AOA1 are not associated with elevated genetic instability and cancer.

Abstract

Hereditary defects in the repair of DNA damage are implicated in a variety of diseases, many of which are typified by neurological dysfunction and/or increased genetic instability and cancer. Of the different types of DNA damage that arise in cells, single-strand breaks (SSBs) are the most common, arising at a frequency of tens of thousands per cell per day from direct attack by intracellular metabolites and from spontaneous DNA decay. Here, the molecular mechanisms and organization of the DNA-repair pathways that remove SSBs are reviewed and the connection between defects in these pathways and hereditary neurodegenerative disease are discussed.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Single-strand breaks and cell fate.
Figure 2: A model for global single-strand break repair.
Figure 3: Common types of damaged single-strand break termini and the enzymes that process them.
Figure 4: A model for replication-coupled single-strand break repair (SSBR).
Figure 5: Aprataxin and ataxia-oculomotor apraxia 1 (AOA1) mutations.
Figure 6: Tyrosyl-DNA phosphodiesterase 1 (TDP1) and spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) mutation.

Similar content being viewed by others

References

  1. Bradley, M. O. & Kohn, K. W. X-ray induced DNA double strand break production and repair in mammalian cells as measured by neutral filter elution. Nucleic Acids Res. 7, 793–804 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Demple, B. & DeMott, M. S. Dynamics and diversions in base excision DNA repair of oxidized abasic lesions. Oncogene 21, 8926–8934 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Hegde, M. L., Hazra, T. K. & Mitra, S. Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells. Cell Res. 18, 27–47 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Pogozelski, W. K. & Tullius, T. D. Oxidative strand scission of nucleic acids: routes initiated by hydrogen abstraction from the sugar moiety. Chem. Rev. 98, 1089–1108 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Wang, J. C. Cellular roles of DNA topoisomerases: a molecular perspective. Nature Rev. Mol. Cell Biol. 3, 430–440 (2002).

    Article  CAS  Google Scholar 

  6. Pommier, Y. et al. Repair of and checkpoint response to topoisomerase I-mediated DNA damage. Mutat. Res. 532, 173–203 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. El-Khamisy, S. F. et al. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature 434, 108–113 (2005). This paper provides the first direct connection between defects in SSBR and neurological disease.

    Article  CAS  PubMed  Google Scholar 

  8. Kouzminova, E. A. & Kuzminov, A. Fragmentation of replicating chromosomes triggered by uracil in DNA. J. Mol. Biol. 355, 20–33 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Kuzminov, A. Single-strand interruptions in replicating chromosomes cause double-strand breaks. Proc. Natl Acad. Sci. USA 98, 8241–8246 (2001). These authors provide supporting evidence for the concept that unrepaired SSBs can lead to DSBs during DNA replication.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bendixen, C., Thomsen, B., Alsner, J. & Westergaard, O. Camptothecin-stabilized topoisomerase I-DNA adducts cause premature termination of transcription. Biochemistry 29, 5613–5619 (1990).

    Article  CAS  PubMed  Google Scholar 

  11. Zhou, W. & Doetsch, P. W. Effects of abasic sites and DNA single-strand breaks on prokaryotic RNA polymerases. Proc. Natl Acad. Sci. USA 90, 6601–6605 (1993). This paper, together with references 12–13, highlights the seminal concept that SSBs can block transcription.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhou, W. & Doetsch, P. W. Transcription bypass or blockage at single-strand breaks on the DNA template strand: effect of different 3′ and 5′ flanking groups on the T7 RNA polymerase elongation complex. Biochemistry 33, 14926–14934 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Kathe, S. D., Shen, G. P. & Wallace, S. S. Single-stranded breaks in DNA but not oxidative DNA base damages block transcriptional elongation by RNA polymerase II in HeLa cell nuclear extracts. J. Biol. Chem. 279, 18511–18520 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Heeres, J. T. & Hergenrother, P. J. Poly(ADP-ribose) makes a date with death. Curr. Opin. Chem. Biol. 11, 644–653 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Moroni, F. Poly(ADP-ribose) polymerase 1 (PARP-1) and postischemic brain damage. Curr. Opin. Pharmacol. 8, 96–103 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. D'Amours, D., Desnoyers, S., D'Silva, I. & Poirier, G. G. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem. J. 342, 249–268 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ame, J. C., Spenlehauer, C. & de Murcia, G. The PARP superfamily. Bioessays 26, 882–893 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Kim, M. Y., Zhang, T. & Kraus, W. L. Poly(ADP-ribosyl)ation by PARP-1: 'PAR-laying' NAD+ into a nuclear signal. Genes Dev. 19, 1951–1967 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Davidovic, L., Vodenicharov, M., Affar, E. B. & Poirier, G. G. Importance of poly(ADP-ribose) glycohydrolase in the control of poly(ADP-ribose) metabolism. Exp. Cell Res. 268, 7–13 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Morgan, W. F. & Cleaver, J. E. Effect of 3-aminobenzamide on the rate of ligation during repair of alkylated DNA in human fibroblasts. Cancer Res. 43, 3104–3107 (1983).

    CAS  PubMed  Google Scholar 

  21. Durkacz, B. W., Omidiji, O., Gray, D. A. & Shall, S. (ADP-ribose)n participates in DNA excision repair. Nature 283, 593–596 (1980).

    Article  CAS  PubMed  Google Scholar 

  22. Parsons, J. L., Dianova, II, Allinson, S. L. & Dianov, G. L. Poly(ADP-ribose) polymerase-1 protects excessive DNA strand breaks from deterioration during repair in human cell extracts. Febs J. 272, 2012–2021 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Mol, C. D., Izumi, T., Mitra, S. & Tainer, J. A. DNA-bound structures and mutants reveal abasic DNA binding by APE1 DNA repair and coordination. Nature 403, 451–456 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Rice, P. A. Holding damaged DNA together. Nature Struct. Biol. 6, 805–806 (1999). References 23 and 24 describe a conceptual framework for the organization of BER.

    Article  CAS  PubMed  Google Scholar 

  25. Wilson, S. H. & Kunkel, T. A. Passing the baton in base excision repair. Nature Struct. Biol. 7, 176–178 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Durkacz, B. W., Shall, S. & Irwin, J. The effect of inhibition of (ADP-ribose)n biosynthesis on DNA repair assayed by the nucleoid technique. Eur. J. Biochem. 121, 65–69 (1981).

    Article  CAS  PubMed  Google Scholar 

  27. James, M. R. & Lehmann, A. R. Role of poly(adenosine diphosphate ribose) in deoxyribonucleic acid repair in human fibroblasts. Biochemistry 21, 4007–4013 (1982).

    Article  CAS  PubMed  Google Scholar 

  28. Lehmann, A. R. & Broughton, B. C. Poly(ADP-ribosylation) reduces the steady-state level of breaks in DNA following treatment of human cells with alkylating agents. Carcinogenesis 5, 117–119 (1984).

    Article  CAS  PubMed  Google Scholar 

  29. Schraufstatter, I. U. et al. Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly(ADP-ribose) polymerase. Proc. Natl Acad. Sci. USA 83, 4908–4912 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fisher, A., Hochegger, H., Takeda, S. & Caldecott, K. W. Poly (ADP-ribose) polymerase-1 accelerates single-strand break repair in concert with poly (ADP-ribose) glycohydrolase. Mol. Cell Biol. 27, 5597–5605 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Le Page, F., Schreiber, V., Dherin, C., De Murcia, G. & Boiteux, S. Poly(ADP-ribose) polymerase-1 (PARP-1) is required in murine cell lines for base excision repair of oxidative DNA damage in the absence of DNA polymerase beta. J. Biol. Chem. 278, 18471–18477 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Trucco, C., Oliver, F. J., de Murcia, G. & Menissier-de Murcia, J. DNA repair defect in poly(ADP-ribose) polymerase-deficient cell lines. Nucleic Acids Res. 26, 2644–2649 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ding, R., Pommier, Y., Kang, V. H. & Smulson, M. Depletion of poly(ADP-ribose) polymerase by antisense RNA expression results in a delay in DNA strand break rejoining. J. Biol. Chem. 267, 12804–12812 (1992).

    CAS  PubMed  Google Scholar 

  34. Gao, H. et al. Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase. Exp. Cell Res. 313, 984–996 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Pleschke, J. M., Kleczkowska, H. E., Strohm, M. & Althaus, F. R. Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins. J. Biol. Chem. 275, 40974–40980 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. El-Khamisy, S. F., Masutani, M., Suzuki, H. & Caldecott, K. W. A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res. 31, 5526–5533 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lan, L. et al. In situ analysis of repair processes for oxidative DNA damage in mammalian cells. Proc. Natl Acad. Sci. USA 101, 13738–13743 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Okano, S., Lan, L., Caldecott, K. W., Mori, T. & Yasui, A. Spatial and temporal cellular responses to single-strand breaks in human cells. Mol. Cell Biol. 23, 3974–3981 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Caldecott, K. W., Aoufouchi, S., Johnson, P. & Shall, S. XRCC1 polypeptide interacts with DNA polymerase beta and possibly poly (ADP-ribose) polymerase, and DNA ligase III is a novel molecular 'nick-sensor' in vitro. Nucleic Acids Res. 24, 4387–4394 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Masson, M. et al. XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol. Cell Biol. 18, 3563–3571 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Caldecott, K. W. XRCC1 and DNA strand break repair. DNA Repair (Amst.) 2, 955–969 (2003).

    Article  CAS  Google Scholar 

  42. Dianov, G. L. & Parsons, J. L. Co-ordination of DNA single strand break repair. DNA Repair (Amst.) 6, 454–460 (2007).

    Article  CAS  Google Scholar 

  43. Poirier, G. G., deMurcia, G., Jongstra-Bilen, J., Niedergang, C. & Mandel, P. Poly(ADP-ribosy)lation of polynucleosomes causes relaxation of chromatin structure. Proc. Natl Acad. Sci. USA 79, 3423–3427 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tulin, A. & Spradling, A. Chromatin loosening by poly(ADP)-ribose polymerase (PARP) at Drosophila puff loci. Science 299, 560–562 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Tulin, A., Stewart, D. & Spradling, A. C. The Drosophila heterochromatic gene encoding poly(ADP-ribose) polymerase (PARP) is required to modulate chromatin structure during development. Genes Dev. 16, 2108–2119 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mathis, G. & Althaus, F. R. Release of core DNA from nucleosomal core particles following (ADP-ribose)n-modification in vitro. Biochem. Biophys. Res. Commun. 143, 1049–1054 (1987).

    Article  CAS  PubMed  Google Scholar 

  47. Caldecott, K. W. Mammalian single-strand break repair: Mechanisms and links with chromatin. DNA Repair (Amst.) 6, 443–453 (2006).

    Article  CAS  Google Scholar 

  48. Dantzer, F. et al. Base excision repair is impaired in mammalian cells lacking Poly(ADP- ribose) polymerase-1. Biochemistry 39, 7559–7569 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Prasad, R. et al. DNA polymerase beta-mediated long patch base excision repair. Poly(ADP-ribose) polymerase-1 stimulates strand displacement DNA synthesis. J. Biol. Chem. 276, 32411–32414 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Sanderson, R. J. & Lindahl, T. Down-regulation of DNA repair synthesis at DNA single-strand interruptions in poly(ADP-ribose) polymerase-1 deficient murine cell extracts. DNA Repair (Amst.) 1, 547–558 (2002).

    Article  CAS  Google Scholar 

  51. Oei, S. L. & Ziegler, M. ATP for the DNA ligation step in base excision repair is generated from poly(ADP-ribose). J. Biol. Chem. 275, 23234–23239 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Petermann, E., Ziegler, M. & Oei, S. L. ATP-dependent selection between single nucleotide and long patch base excision repair. DNA Repair (Amst.) 2, 1101–1114 (2003).

    Article  CAS  Google Scholar 

  53. Lindahl, T., Satoh, M. S., Poirier, G. G. & Klungland, A. Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem. Sci. 20, 405–411 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Sobol, R. W. et al. The lyase activity of the DNA repair protein beta-polymerase protects from DNA-damage-induced cytotoxicity. Nature 405, 807–810 (2000). This is an important paper that demonstrated the significance of Pol b in repairing damaged SSB termini.

    Article  CAS  PubMed  Google Scholar 

  55. Roth, R. B. & Samson, L. D. 3-Methyladenine DNA glycosylase-deficient Aag null mice display unexpected bone marrow alkylation resistance. Cancer Res. 62, 656–660 (2002).

    CAS  PubMed  Google Scholar 

  56. Trivedi, R. N. et al. Human methyl purine DNA glycosylase and DNA polymerase beta expression collectively predict sensitivity to temozolomide. Mol. Pharmacol. 13 May 2008 (doi:10.1124/mol.108.045112).

    Article  CAS  PubMed  Google Scholar 

  57. Sobol, R. W. et al. Base excision repair intermediates induce p53-independent cytotoxic and genotoxic responses. J. Biol. Chem. 278, 39951–39959 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Whitehouse, C. J. et al. XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell 104, 107–117 (2001). These authors describe the first indication of the most important role identified for XRCC1 so far — promoting the processing of damaged DNA termini.

    Article  CAS  PubMed  Google Scholar 

  59. Karimi-Busheri, F. et al. Molecular characterization of a human DNA kinase. J. Biol. Chem. 274, 24187–24194 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Jilani, A. et al. Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3′-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage. J. Biol. Chem. 274, 24176–24186 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Winters, T. A., Weinfeld, M. & Jorgensen, T. J. Human HeLa cell enzymes that remove phosphoglycolate 3′-end groups from DNA. Nucleic Acids Res. 20, 2573–2580 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Winters, T. A., Henner, W. D., Russell, P. S., McCullough, A. & Jorgensen, T. J. Removal of 3′-phosphoglycolate from DNA strand-break damage in an oligonucleotide substrate by recombinant human apurinic/apyrimidinic endonuclease 1. Nucleic Acids Res. 22, 1866–1873 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen, D. S., Herman, T. & Demple, B. Two distinct human DNA diesterases that hydrolyze 3′-blocking deoxyribose fragments from oxidized DNA. Nucleic Acids Res. 19, 5907–5914 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Izumi, T. et al. Requirement for human AP endonuclease 1 for repair of 3′-blocking damage at DNA single-strand breaks induced by reactive oxygen species. Carcinogenesis 21, 1329–1334 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Parsons, J. L., Dianova, I. I. & Dianov, G. L. APE1 is the major 3′-phosphoglycolate activity in human cell extracts. Nucleic Acids Res. 32, 3531–3536 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Matsumoto, Y. & Kim, K. Excision of deoxyribose phosphate residues by DNA polymerase beta during DNA repair. Science 269, 699–702 (1995).

    Article  CAS  PubMed  Google Scholar 

  67. Sung, J. S. & Demple, B. Roles of base excision repair subpathways in correcting oxidized abasic sites in DNA. Febs J. 273, 1620–1629 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Wiederhold, L. et al. AP endonuclease-independent DNA base excision repair in human cells. Mol. Cell 15, 209–220 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Yang, S. W. et al. A eukaryotic enzyme that can disjoin dead-end covalent complexes between DNA and type I topoisomerases. Proc. Natl. Acad. Sci. USA 93, 11534–11539 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Pouliot, J. J., Yao, K. C., Robertson, C. A. & Nash, H. A. Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes. Science 286, 552–555 (1999). This paper contains the seminal finding that TDP1 is an end-processing factor.

    Article  CAS  PubMed  Google Scholar 

  71. Ahel, I. et al. The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates. Nature 443, 713–716 (2006). These authors describe the seminal finding that 5′-AMP strand breaks are the likely physiological substrate for APTX.

    Article  CAS  PubMed  Google Scholar 

  72. Rass, U., Ahel, I. & West, S. C. Actions of aprataxin in multiple DNA repair pathways. J. Biol. Chem. 282, 9469–9474 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Loizou, J. I. et al. The protein kinase CK2 facilitates repair of chromosomal DNA single-strand breaks. Cell 117, 17–28 (2004). This paper contains the seminal finding that CK2 is a DNA repair protein and is required to assemble XRCC1 end-processing complexes.

    Article  CAS  PubMed  Google Scholar 

  74. Clements, P. M. et al. The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4. DNA Repair (Amst.) 3, 1493–1502 (2004). This paper and references 75–77 establish APTX as a component of the SSBR machinery.

    Article  CAS  Google Scholar 

  75. Gueven, N. et al. Aprataxin, a novel protein that protects against genotoxic stress. Hum. Mol. Genet. 13, 1081–1093 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Luo, H. et al. A new XRCC1-containing complex and its role in cellular survival of methyl methanesulfonate treatment. Mol. Cell Biol. 24, 8356–8365 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sano, Y. et al. Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein. Ann. Neurol. 55, 241–249 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Kubota, Y. et al. Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein. EMBO J. 15, 6662–6670 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Plo, I. et al. Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions. DNA Repair (Amst.) 2, 1087–1100 (2003).

    Article  CAS  Google Scholar 

  80. Sossou, M. et al. APE1 overexpression in XRCC1-deficient cells complements the defective repair of oxidative single strand breaks but increases genomic instability. Nucleic Acids Res. 33, 298–306 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mani, R. S. et al. XRCC1 stimulates polynucleotide kinase by enhancing its damage discrimination and displacement from DNA repair intermediates. J. Biol. Chem. 282, 28004–28013 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Hirano, M. et al. DNA single-strand break repair is impaired in aprataxin-related ataxia. Ann. Neurol. 61, 162–174 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Fortini, P., Pascucci, B., Belisario, F. & Dogliotti, E. DNA polymerase beta is required for efficient DNA strand break repair induced by methyl methanesulfonate but not by hydrogen peroxide. Nucleic Acids Res. 28, 3040–3046 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Pascucci, B., Russo, M. T., Crescenzi, M., Bignami, M. & Dogliotti, E. The accumulation of MMS-induced single strand breaks in G1 phase is recombinogenic in DNA polymerase beta defective mammalian cells. Nucleic Acids Res. 33, 280–288 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Vermeulen, C., Verwijs-Janssen, M., Cramers, P., Begg, A. C. & Vens, C. Role for DNA polymerase beta in response to ionizing radiation. DNA Repair (Amst.) 6, 202–212 (2007).

    Article  CAS  Google Scholar 

  86. Braithwaite, E. K. et al. DNA polymerase lambda protects mouse fibroblasts against oxidative DNA damage and is recruited to sites of DNA damage/repair. J. Biol. Chem. 280, 31641–31647 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Garcia-Diaz, M., Bebenek, K., Kunkel, T. A. & Blanco, L. 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 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Bebenek, K. et al. 5′-Deoxyribose phosphate lyase activity of human DNA polymerase iota in vitro. Science 291, 2156–2159 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Prasad, R., Dianov, G. L., Bohr, V. A. & Wilson, S. H. FEN1 stimulation of DNA polymerase beta mediates an excision step in mammalian long patch base excision repair. J. Biol. Chem. 275, 4460–4466 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Hashiguchi, K., Matsumoto, Y. & Yasui, A. Recruitment of DNA repair synthesis machinery to sites of DNA damage/repair in living human cells. Nucleic Acids Res. 35, 2913–2923 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Frosina, G. et al. Two pathways for base excision repair in mammalian cells. J. Biol. Chem. 271, 9573–9578 (1996). These data underpin the concept of long-patch and short-patch BER.

    Article  CAS  PubMed  Google Scholar 

  92. Klungland, A. & Lindahl, T. Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1). Embo J. 16, 3341–3348 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Fan, J., Otterlei, M., Wong, H. K., Tomkinson, A. E. & Wilson, D. M. 3rd. XRCC1 co-localizes and physically interacts with PCNA. Nucleic Acids Res. 32, 2193–2201 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Uchiyama, Y., Suzuki, Y. & Sakaguchi, K. Characterization of plant XRCC1 and its interaction with proliferating cell nuclear antigen. Planta 227, 1233–1241 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Cotner-Gohara, E., Kim, I. K., Tomkinson, A. E. & Ellenberger, T. Two DNA binding and nick recognition modules in human DNA ligase III. J. Biol. Chem. 283, 10764–10772 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lakshmipathy, U. & Campbell, C. Antisense-mediated decrease in DNA ligase III expression results in reduced mitochondrial DNA integrity. Nucleic Acids Res. 29, 668–676 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. De, A. & Campbell, C. A novel interaction between DNA ligase III and DNA polymerase gamma plays an essential role in mitochondrial DNA stability. Biochem. J. 402, 175–186 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mortusewicz, O., Rothbauer, U., Cardoso, M. C. & Leonhardt, H. Differential recruitment of DNA ligase I and III to DNA repair sites. Nucleic Acids Res. 34, 3523–3532 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Caldecott, K. W., Tucker, J. D., Stanker, L. H. & Thompson, L. H. Characterization of the XRCC1-DNA ligase III complex in vitro and its absence from mutant hamster cells. Nucleic Acids Res. 23, 4836–4843 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wei, Y. F. et al. Molecular cloning and expression of human cDNAs encoding a novel DNA ligase IV and DNA ligase III, an enzyme active in DNA repair and recombination. Mol. Cell Biol. 15, 3206–3216 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Taylor, R. M., Whitehouse, C. J. & Caldecott, K. W. The DNA ligase III zinc finger stimulates binding to DNA secondary structure and promotes end joining. Nucleic Acids Res. 28, 3558–3563 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Taylor, R. M., Whitehouse, J., Cappelli, E., Frosina, G. & Caldecott, K. W. Role of the DNA ligase III zinc finger in polynucleotide binding and ligation. Nucleic Acids Res. 26, 4804–4810 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Mackey, Z. B. et al. DNA ligase III is recruited to DNA strand breaks by a zinc finger motif homologous to that of poly(ADP-ribose) polymerase. Identification of two functionally distinct DNA binding regions within DNA ligase III. J. Biol. Chem. 274, 21679–21687 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Wang, H. et al. DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. Cancer Res. 65, 4020–4030 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Audebert, M., Salles, B. & Calsou, P. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Wong, H. K., Kim, D., Hogue, B. A., McNeill, D. R. & Wilson, D. M. 3rd. DNA damage levels and biochemical repair capacities associated with XRCC1 deficiency. Biochemistry 44, 14335–14343 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Bekker-Jensen, S. et al. Human Xip1 (C2orf13) is a novel regulator of cellular responses to DNA strand breaks. J. Biol. Chem. 282, 19638–19643 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Iles, N., Rulten, S., El-Khamisy, S. F. & Caldecott, K. W. APLF (C2orf13) is a novel human protein involved in the cellular response to chromosomal dna strand breaks. Mol. Cell Biol. 27, 3793–3803 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Schreiber, V. et al. Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J. Biol. Chem. 277, 23028–23036 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Tan, Y., Raychaudhuri, P. & Costa, R. H. Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. Mol. Cell Biol. 27, 1007–1016 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Li, N., Wu, H., Yang, S. & Chen, D. Ischemic preconditioning induces XRCC1, DNA polymerase-beta, and DNA ligase III and correlates with enhanced base excision repair. DNA Repair (Amst.) 6, 1297–306 (2007).

    Article  CAS  Google Scholar 

  112. Fritz, G., Grosch, S., Tomicic, M. & Kaina, B. APE/Ref-1 and the mammalian response to genotoxic stress. Toxicology 193, 67–78 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Hasan, S. et al. Acetylation regulates the DNA end-trimming activity of DNA polymerase beta. Mol. Cell 10, 1213–1222 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Parsons, J. L. et al. CHIP-mediated degradation and DNA damage-dependent stabilization regulate base excision repair proteins. Mol. Cell 29, 477–487 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Chen, D., Yu, Z., Zhu, Z. & Lopez, C. D. E2F1 regulates the base excision repair gene XRCC1 and promotes DNA repair. J. Biol. Chem. 283, 15381–15389 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Narciso, L. et al. Terminally differentiated muscle cells are defective in base excision DNA repair and hypersensitive to oxygen injury. Proc. Natl Acad. Sci. USA 104, 17010–17015 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Otterlei, M. et al. Post-replicative base excision repair in replication foci. EMBO J. 18, 3834–3844 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Parlanti, E., Locatelli, G., Maga, G. & Dogliotti, E. Human base excision repair complex is physically associated to DNA replication and cell cycle regulatory proteins. Nucleic Acids Res. 35, 1569–1577 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Moore, D. J., Taylor, R. M., Clements, P. & Caldecott, K. W. Mutation of a BRCT domain selectively disrupts DNA single-strand break repair in noncycling Chinese hamster ovary cells. Proc. Natl Acad. Sci. USA 97, 13649–13654 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Taylor, R. M., Moore, D. J., Whitehouse, J., Johnson, P. & Caldecott, K. W. A cell cycle-specific requirement for the XRCC1 BRCT II domain during mammalian DNA strand break repair. Mol. Cell Biol. 20, 735–740 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Caldecott, K. W. Mammalian DNA single-strand break repair: an X-ra(y)ted affair. Bioessays 23, 447–455 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. Caldecott, K. W. DNA single-strand break repair and spinocerebellar ataxia. Cell 112, 7–10 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Caldecott, K. W. DNA single-strand breaks and neurodegeneration. DNA Repair (Amst.) 3, 875–882 (2004).

    Article  CAS  Google Scholar 

  124. Aicardi, J. et al. Ataxia-ocular motor apraxia: a syndrome mimicking ataxia-telangiectasia. Ann. Neurol. 24, 497–502 (1988).

    Article  CAS  PubMed  Google Scholar 

  125. Hannan, M. A., Sigut, D., Waghray, M. & Gascon, G. G. Ataxia-ocular motor apraxia syndrome: an investigation of cellular radiosensitivity of patients and their families. J. Med. Genet. 31, 953–956 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Barbot, C. et al. Recessive ataxia with ocular apraxia: review of 22 Portuguese patients. Arch. Neurol. 58, 201–205 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Moreira, M. C. et al. Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13, and evidence for genetic heterogeneity. Am. J. Hum. Genet. 68, 501–508 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Le Ber, I. et al. Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies. Brain 126, 2761–2772 (2003).

    Article  PubMed  Google Scholar 

  129. Baba, Y. et al. Aprataxin (APTX) gene mutations resembling multiple system atrophy. Parkinsonism Relat. Disord. 13, 139–142 (2006).

    Article  PubMed  Google Scholar 

  130. Quinzii, C. M. et al. Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation. Neurology 64, 539–541 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Le Ber, I. et al. Muscle coenzyme Q10 deficiencies in ataxia with oculomotor apraxia 1. Neurology 68, 295–297 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Date, H. et al. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene. Nature Genet. 29, 184–188 (2001). This paper and reference 133 identified APTX as the protein mutated in AOA1.

    Article  CAS  PubMed  Google Scholar 

  133. Moreira, M. C. et al. The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nature Genet. 29, 189–193 (2001).

    Article  CAS  PubMed  Google Scholar 

  134. Habeck, M. et al. Aprataxin mutations are a rare cause of early onset ataxia in Germany. J. Neurol. 251, 591–594 (2004).

    Article  CAS  PubMed  Google Scholar 

  135. Date, H. et al. The FHA domain of aprataxin interacts with the C-terminal region of XRCC1. Biochem. Biophys. Res. Commun. 325, 1279–1285 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Kanno, S. et al. A novel human AP endonuclease with conserved zinc-finger-like motifs involved in DNA strand break responses. Embo J. 26, 2094–2103 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Koch, C. A. et al. Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA ligation by DNA ligase IV. Embo J. 23, 3874–3885 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Becherel, O. J. et al. Nucleolar localization of aprataxin is dependent on interaction with nucleolin and on active ribosomal DNA transcription. Hum. Mol. Genet. 15, 2239–2249 (2006).

    Article  CAS  PubMed  Google Scholar 

  139. Seidle, H. F., Bieganowski, P. & Brenner, C. Disease-associated mutations inactivate AMP-lysine hydrolase activity of Aprataxin. J. Biol. Chem. 280, 20927–20931 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Hirano, M. et al. Short half-lives of ataxia-associated aprataxin proteins in neuronal cells. Neurosci. Lett. 419, 184–187 (2007).

    Article  CAS  PubMed  Google Scholar 

  141. Criscuolo, C. et al. Very late onset in ataxia oculomotor apraxia type I. Ann. Neurol. 57, 777 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. Criscuolo, C. et al. Ataxia with oculomotor apraxia type 1 in southern Italy: late onset and variable phenotype. Neurology 63, 2173–2175 (2004).

    Article  CAS  PubMed  Google Scholar 

  143. Tranchant, C., Fleury, M., Moreira, M. C., Koenig, M. & Warter, J. M. Phenotypic variability of aprataxin gene mutations. Neurology 60, 868–870 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. Kijas, A. W., Harris, J. L., Harris, J. M. & Lavin, M. F. Aprataxin forms a discrete branch in the HIT (histidine triad) superfamily of proteins with both DNA/RNA binding and nucleotide hydrolase activities. J. Biol. Chem. 281, 13939–13948 (2006).

    Article  CAS  PubMed  Google Scholar 

  145. Rass, U., Ahel, I. & West, S. C. Defective DNA repair and neurodegenerative disease. Cell 130, 991–1004 (2007).

    Article  CAS  PubMed  Google Scholar 

  146. Takashima, H. et al. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nature Genet. 32, 267–272 (2002). This paper identified TDP1 as the protein mutated in SCAN1.

    Article  CAS  PubMed  Google Scholar 

  147. Pourquier, P. et al. Trapping of mammalian topoisomerase I and recombinations induced by damaged DNA containing nicks or gaps. Importance of DNA end phosphorylation and camptothecin effects. J. Biol. Chem. 272, 26441–26447 (1997).

    Article  CAS  PubMed  Google Scholar 

  148. Pourquier, P. et al. Induction of reversible complexes between eukaryotic DNA topoisomerase I and DNA-containing oxidative base damages. 7,8-dihydro-8-oxoguanine and 5-hydroxycytosine. J. Biol. Chem. 274, 8516–8523 (1999).

    Article  CAS  PubMed  Google Scholar 

  149. Pourquier, P. et al. Effects of uracil incorporation, DNA mismatches, and abasic sites on cleavage and religation activities of mammalian topoisomerase I. J. Biol. Chem. 272, 7792–7796 (1997).

    Article  CAS  PubMed  Google Scholar 

  150. Pourquier, P. et al. Topoisomerase I-mediated cytotoxicity of N-methyl-N′-nitro-N-nitrosoguanidine: trapping of topoisomerase I by the O6-methylguanine. Cancer Res. 61, 53–58 (2001).

    CAS  PubMed  Google Scholar 

  151. Pourquier, P. & Pommier, Y. Topoisomerase I-mediated DNA damage. Adv. Cancer Res. 80, 189–216 (2001).

    Article  CAS  PubMed  Google Scholar 

  152. Lebedeva, N., Auffret Vander Kemp, P., Bjornsti, M. A., Lavrik, O. & Boiteux, S. Trapping of DNA topoisomerase I on nick-containing DNA in cell free extracts of Saccharomyces cerevisiae. DNA Repair (Amst.) 5, 799–809 (2006).

    Article  CAS  Google Scholar 

  153. Daroui, P., Desai, S. D., Li, T. K., Liu, A. A. & Liu, L. F. Hydrogen peroxide induces topoisomerase I-mediated DNA damage and cell death. J. Biol. Chem. 279, 14587–14594 (2004).

    Article  CAS  PubMed  Google Scholar 

  154. Nitiss, J. L., Nitiss, K. C., Rose, A. & Waltman, J. L. Overexpression of type I topoisomerases sensitizes yeast cells to DNA damage. J. Biol. Chem. 276, 26708–26714 (2001).

    Article  CAS  PubMed  Google Scholar 

  155. Liu, C., Pouliot, J. J. & Nash, H. A. The role of TDP1 from budding yeast in the repair of DNA damage. DNA Repair (Amst.) 3, 593–601 (2004).

    Article  CAS  Google Scholar 

  156. El-Khamisy, S. F., Hartsuiker, E. & Caldecott, K. W. TDP1 facilitates repair of ionizing radiation-induced DNA single-strand breaks. DNA Repair (Amst.) 6, 1485–1495 (2007).

    Article  CAS  Google Scholar 

  157. Inamdar, K. V. et al. Conversion of phosphoglycolate to phosphate termini on 3′ overhangs of DNA double strand breaks by the human tyrosyl-DNA phosphodiesterase hTdp1. J. Biol. Chem. 277, 27162–27168 (2002).

    Article  CAS  PubMed  Google Scholar 

  158. Interthal, H., Chen, H. J. & Champoux, J. J. Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages. J. Biol. Chem. 280, 36518–36528 (2005).

    Article  CAS  PubMed  Google Scholar 

  159. Zhou, T. et al. Deficiency in 3′-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1). Nucleic Acids Res. 33, 289–297 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Nitiss, K. C., Malik, M., He, X., White, S. W. & Nitiss, J. L. Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage. Proc. Natl Acad. Sci. USA 103, 8953–8958 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Interthal, H. et al. SCAN1 mutant Tdp1 accumulates the enzyme–DNA intermediate and causes camptothecin hypersensitivity. Embo J. 24, 2224–2233 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Hirano, R. et al. Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation? Embo J. 26, 4732–4743 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Katyal, S. et al. TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo. Embo J. 26, 4720–4731 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Mosesso, P. et al. The novel human gene aprataxin is directly involved in DNA single-strand-break repair. Cell. Mol. Life Sci. 62, 485–491 (2005).

    Article  CAS  PubMed  Google Scholar 

  165. El-Khamisy, S. F. & Caldecott, K. W. TDP1-dependent DNA single-strand break repair and neurodegeneration. Mutagenesis 21, 219–224 (2006).

    Article  CAS  PubMed  Google Scholar 

  166. Sweasy, J. B., Lang, T. & DiMaio, D. Is base excision repair a tumor suppressor mechanism? Cell Cycle 5, 250–259 (2006).

    Article  CAS  PubMed  Google Scholar 

  167. Barzilai, A., Rotman, G. & Shiloh, Y. ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage. DNA Repair (Amst.) 1, 3–25 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I thank the MRC, BBSRC, and EU for financial support, and members of my laboratory for comments and suggestions. I apologize to my colleagues for work I have not referenced in this article, this is due to restrictions in citation numbers.

Author information

Authors and Affiliations

Authors

Related links

Related links

DATABASES

OMIM

ataxia-oculomotor apraxia 1

ataxia-telangiectasia

Friedreich ataxia

spinocerebellar ataxia with axonal neuropathy 1

FURTHER INFORMATION

Sussex Centre for Genome Damage and Stability

Glossary

Alternative non homologous end joining

Also known as back-up non homologous end joining. A subpathway of non homologous end joining (NHEJ) that does not require classical NHEJ proteins and which might rejoin DSBs located within short regions of microhomology.

Clastogenic

Capable of causing chromosome damage and/or rearrangements.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Caldecott, K. Single-strand break repair and genetic disease. Nat Rev Genet 9, 619–631 (2008). https://doi.org/10.1038/nrg2380

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2380

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing