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Cited by 6DNA Repair MechanismsEffects of Radiation ExposurePARP inhibition in cancer therapy

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SNM1A is crucial for efficient repair of complex DNA breaks in human cells

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Swift, Lonnie P., Lagerholm, B. Christoffer, Henderson, Lucy R., Ratnaweera, Malitha, Baddock, Hannah T., Sengerova, Blanka, Lee, Sook, Cruz-Migoni, Abimael, Waithe, Dominic, Renz, Christian, Ulrich, Helle D., Newman, Joseph A., Schofield, Christopher J., McHugh, Peter J.·2024·Nature Communications
DOI 10.1038/s41467-024-49583-5PMC PMC11199599

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Abstract

DNA double-strand breaks (DSBs), such as those produced by radiation and radiomimetics, are amongst the most toxic forms of cellular damage, in part because they involve extensive oxidative modifications at the break termini. Prior to completion of DSB repair, the chemically modified termini must be removed. Various DNA processing enzymes have been implicated in the processing of these dirty ends, but molecular knowledge of this process is limited. Here, we demonstrate a role for the metallo-β-lactamase fold 5′−3′ exonuclease SNM1A in this vital process. Cells disrupted for SNM1A manifest increased sensitivity to radiation and radiomimetic agents and show defects in DSB damage repair. SNM1A is recruited and is retained at the sites of DSB damage via the concerted action of its three highly conserved PBZ, PIP box and UBZ interaction domains, which mediate interactions with poly-ADP-ribose chains, PCNA and the ubiquitinated form of PCNA, respectively. SNM1A can resect DNA containing oxidative lesions induced by radiation damage at break termini. The combined results reveal a crucial role for SNM1A to digest chemically modified DNA during the repair of DSBs and imply that the catalytic domain of SNM1A is an attractive target for potentiation of radiotherapy.

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Research works printed but not linked: 66

  1. Scully, R., Panday, A., Elango, R. & Willis, N. A. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat. Rev. Mol. Cell Biol. 20, 698–714 (2019). · DOI
  2. Chapman, J. R., Taylor, M. R. & Boulton, S. J. Playing the end game: DNA double-strand break repair pathway choice. Mol. cell 47, 497–510 (2012). · DOI
  3. Shibata, A. & Jeggo, P. A historical reflection on our understanding of radiation-induced DNA double strand break repair in somatic mammalian cells; interfacing the past with the present. Int. J. Radiat. Biol. 95, 945–956 (2019). · DOI
  4. Kieffer, S. R. & Lowndes, N. F. Immediate-early, early, and late responses to DNA double stranded breaks. Front. Genet. 13, 793884 (2022). · DOI
  5. 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). · DOI
  6. Chappell, C., Hanakahi, L. A., Karimi-Busheri, F., Weinfeld, M. & West, S. C. Involvement of human polynucleotide kinase in double-strand break repair by non-homologous end joining. EMBO J. 21, 2827–2832 (2002). · DOI
  7. Rass, U., Ahel, I. & West, S. C. Actions of aprataxin in multiple DNA repair pathways. J. Biol. Chem. 282, 9469–9474 (2007). · DOI
  8. Takahashi, T. et al. Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3’-phosphate and 3’-phosphoglycolate ends. Nucleic Acids Res. 35, 3797–3809 (2007). · DOI
  9. Gueven, N. et al. Aprataxin, a novel protein that protects against genotoxic stress. Hum. Mol. Genet. 13, 1081–1093 (2004). · DOI
  10. 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). · DOI
  11. Moshous, D. et al. 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 (2001). · DOI
  12. Ma, Y., Pannicke, U., Schwarz, K. & Lieber, M. R. 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 (2002). · DOI · Paper page
  13. 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). · DOI
  14. Ahel, I. et al. The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates. Nature 443, 713–716 (2006). · DOI
  15. Baddock, H. T. et al. The SNM1A DNA repair nuclease. DNA repair 95, 102941 (2020). · DOI
  16. Pettinati, I., Brem, J., Lee, S. Y., McHugh, P. J. & Schofield, C. J. The chemical biology of human metallo-beta-lactamase fold proteins. Trends Biochem. Sci. 41, 338–355 (2016). · DOI
  17. Wang, A. T. et al. Human SNM1A and XPF-ERCC1 collaborate to initiate DNA interstrand cross-link repair. Genes Dev. 25, 1859–1870 (2011). · DOI
  18. Yang, K., Moldovan, G. L. & D’Andrea, A. D. RAD18-dependent recruitment of SNM1A to DNA repair complexes by a ubiquitin-binding zinc finger. J. Biol. Chem. 285, 19085–19091 (2010). · DOI
  19. Zhang, T. et al. Break-induced replication orchestrates resection-dependent template switching. Nature 619, 201–208 (2023). · DOI
  20. Schmiester, M. & Demuth, I. SNM1B/Apollo in the DNA damage response and telomere maintenance. Oncotarget 8, 48398–48409 (2017). · DOI
  21. Baddock, H. T. et al. A phosphate binding pocket is a key determinant of exo- versus endo-nucleolytic activity in the SNM1 nuclease family. Nucleic acids Res. 49, 9294–9309 (2021). · DOI
  22. Pannicke, U. et al. Functional and biochemical dissection of the structure-specific nuclease ARTEMIS. EMBO J. 23, 1987–1997 (2004). · DOI · Paper page
  23. Porteus, M. Design and testing of zinc finger nucleases for use in mammalian cells. Methods Mol. Biol. 435, 47–61 (2008). · DOI
  24. Doudna, J. A. & Charpentier, E. The new frontier of genome engineering with CRISPR-Cas9. Science 346, 1258096 (2014). · DOI · Paper page
  25. Povirk, L. F. DNA damage and mutagenesis by radiomimetic DNA-cleaving agents: bleomycin, neocarzinostatin and other enediynes. Mutat. Res. 355, 71–89 (1996). · DOI
  26. Scully, R. & Xie, A. Double strand break repair functions of histone H2AX. Mutat. Res. 750, 5–14 (2013). · DOI
  27. Zimmermann, M. & de Lange, T. 53BP1: pro choice in DNA repair. Trends Cell Biol. 24, 108–117 (2014). · DOI
  28. Hopfner, K. P., Putnam, C. D. & Tainer, J. A. DNA double-strand break repair from head to tail. Curr. Opin. Struct. Biol. 12, 115–122 (2002). · DOI
  29. Jasin, M. Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Oncogene 21, 8981–8993 (2002). · DOI
  30. Iacovoni, J. S. et al. High-resolution profiling of gammaH2AX around DNA double strand breaks in the mammalian genome. EMBO J. 29, 1446–1457 (2010). · DOI · Paper page
  31. Ahel, I. et al. Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins. Nature 451, 81–85 (2008). · DOI
  32. Hurley, J. H., Lee, S. & Prag, G. Ubiquitin-binding domains. Biochem. J. 399, 361–372 (2006). · DOI
  33. De Biasio, A. & Blanco, F. J. Proliferating cell nuclear antigen structure and interactions: too many partners for one dancer? Adv. Protein Chem. Struct. Biol. 91, 1–36 (2013). · DOI
  34. Rizzo, A. A., Salerno, P. E., Bezsonova, I. & Korzhnev, D. M. NMR structure of the human Rad18 zinc finger in complex with ubiquitin defines a class of UBZ domains in proteins linked to the DNA damage response. Biochemistry 53, 5895–5906 (2014). · DOI
  35. Eustermann, S. et al. Solution structures of the two PBZ domains from human APLF and their interaction with poly(ADP-ribose). Nat. Struct. Mol. Biol. 17, 241–243 (2010). · DOI
  36. Gulbis, J. M., Kelman, Z., Hurwitz, J., O’Donnell, M. & Kuriyan, J. Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA. Cell 87, 297–306 (1996). · DOI
  37. Botchway, S. W., Reynolds, P., Parker, A. W. & O’Neill, P. Laser-induced radiation microbeam technology and simultaneous real-time fluorescence imaging in live cells. Methods Enzymol. 504, 3–28 (2012). · DOI
  38. Traenkle, B. & Rothbauer, U. Under the microscope: single-domain antibodies for live-cell imaging and super-resolution microscopy. Front. Immunol. 8, 1030 (2017). · DOI
  39. Ulrich, H. D. Regulating post-translational modifications of the eukaryotic replication clamp PCNA. DNA Repair 8, 461–469 (2009). · DOI
  40. Lee, D. H. & Goldberg, A. L. Proteasome inhibitors: valuable new tools for cell biologists. Trends Cell Biol. 8, 397–403 (1998). · DOI · Paper page
  41. Thakar, T. et al. Ubiquitinated-PCNA protects replication forks from DNA2-mediated degradation by regulating Okazaki fragment maturation and chromatin assembly. Nat. Commun. 11, 2147 (2020). · DOI
  42. D’Andrea, A. D. Mechanisms of PARP inhibitor sensitivity and resistance. DNA Repair 71, 172–176 (2018). · DOI
  43. Sengerova, B. et al. Characterization of the human SNM1A and SNM1B/Apollo DNA repair exonucleases. J. Biol. Chem. 287, 26254–26267 (2012). · DOI
  44. Cadet, J., Douki, T., Gasparutto, D. & Ravanat, J. L. Oxidative damage to DNA: formation, measurement and biochemical features. Mutat. Res. 531, 5–23 (2003). · DOI
  45. Chen, J. & Stubbe, J. Bleomycins: towards better therapeutics. Nat. Rev. Cancer 5, 102–112 (2005). · DOI
  46. Huang, J. et al. RAD18 transmits DNA damage signalling to elicit homologous recombination repair. Nat. Cell Biol. 11, 592–603 (2009). · DOI
  47. Fan, L., Bi, T., Wang, L. & Xiao, W. DNA-damage tolerance through PCNA ubiquitination and sumoylation. Biochem. J. 477, 2655–2677 (2020). · DOI
  48. Raschle, M. et al. Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links. Science 348, 1253671 (2015). · DOI
  49. Dronkert, M. L. et al. Disruption of mouse SNM1 causes increased sensitivity to the DNA interstrand cross-linking agent mitomycin C. Mol. Cell Biol. 20, 4553–4561 (2000). · DOI
  50. Ahkter, S. et al. Snm1-deficient mice exhibit accelerated tumorigenesis and susceptibility to infection. Mol. Cell Biol. 25, 10071–10078 (2005). · DOI
  51. Ishiai, M. et al. DNA cross-link repair protein SNM1A interacts with PIAS1 in nuclear focus formation. Mol. Cell Biol. 24, 10733–10741 (2004). · DOI
  52. Richie, C. T. et al. hSnm1 colocalizes and physically associates with 53BP1 before and after DNA damage. Mol. Cell Biol. 22, 8635–8647 (2002). · DOI
  53. Demuth, I., Digweed, M. & Concannon, P. Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation. Oncogene 23, 8611–8618 (2004). · DOI
  54. Lam, A. F., Krogh, B. O. & Symington, L. S. Unique and overlapping functions of the Exo1, Mre11 and Pso2 nucleases in DNA repair. DNA Repair 7, 655–662 (2008). · DOI
  55. Sacho, E. J. & Maizels, N. DNA repair factor MRE11/RAD50 cleaves 3’-phosphotyrosyl bonds and resects DNA to repair damage caused by topoisomerase 1 poisons. J. Biol. Chem. 286, 44945–44951 (2011). · DOI
  56. Hartsuiker, E., Neale, M. J. & Carr, A. M. Distinct requirements for the Rad32(Mre11) nuclease and Ctp1(CtIP) in the removal of covalently bound topoisomerase I and II from DNA. Mol. Cell 33, 117–123 (2009). · DOI
  57. Mirdita, M. et al. ColabFold: making protein folding accessible to all. Nat. Methods 19, 679–682 (2022). · DOI · Paper page
  58. Pettersen, E. F. et al. UCSF ChimeraX: Structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021). · DOI
  59. Ramkumar, N. & Baum, B. Coupling changes in cell shape to chromosome segregation. Nat. Rev. Mol. cell Biol. 17, 511–521 (2016). · DOI
  60. Huang, L. K. & Wang, M. J. J. Image thresholding by minimizing the measures of fuzziness. Pattern Recogn. 28, 41–51 (1995). · DOI
  61. Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012). · DOI · Paper page
  62. Hibbert, R. G. & Sixma, T. K. Intrinsic flexibility of ubiquitin on proliferating cell nuclear antigen (PCNA) in translesion synthesis. J. Biol. Chem. 287, 39216–39223 (2012). · DOI
  63. Genschel, J., Bazemore, L. R. & Modrich, P. Human exonuclease I is required for 5’ and 3’ mismatch repair. J. Biol. Chem. 277, 13302–13311 (2002). · DOI
  64. Pastwa, E., Neumann, R. D. & Winters, T. A. In vitro repair of complex unligatable oxidatively induced DNA double-strand breaks by human cell extracts. Nucleic Acids Res. 29, E78 (2001). · DOI
  65. Pierce, A. J., Johnson, R. D., Thompson, L. H. & Jasin, M. XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes Dev. 13, 2633–2638 (1999). · DOI
  66. Bennardo, N., Cheng, A., Huang, N. & Stark, J. M. Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet. 4, e1000110 (2008). · DOI

Metadata

Authors
Swift, L. P., Lagerholm, B. C., Henderson, L. R., Ratnaweera, M., Baddock, H. T., Sengerova, B., Lee, S., Cruz-Migoni, A., Waithe, D., Renz, C., Ulrich, H. D., Newman, J. A., Schofield, C. J., & McHugh, P. J.
Affiliations
  • John Radcliffe Hospital (GB)
  • Åbo Akademi University (FI)
  • Institute of Molecular Biology (DE)
  • University of Oxford (GB)
Corresponding author
McHugh, Peter J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-06-25
Volume
15
Issue
1
Pages
5392-5392
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-49583-5
PMC
PMC11199599
OpenAlex
W4399996483
Cited by
6
References
1
Citations by year
2026: 2 · 2025: 3 · 2024: 1
FWCI
0.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Åbo Akademi University Research Portal (submittedVersion, cc-by)
  • UTUPub (University of Turku) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Cancer Research UK (CRUK/ A24759)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Keywords
DNA double-strand break repair, DNA end resection, oxidative DNA damage, 5'-3' exonuclease, PIP box, poly(ADP-ribose), PCNA, radiosensitivity, radiomimetic agents, radiosensitization, chemically modified DNA
MeSH terms
DNA, DNA Repair, Exodeoxyribonucleases, Humans, Cell Cycle Proteins, Proliferating Cell Nuclear Antigen, DNA Repair Enzymes, DNA Breaks, Double-Stranded, Ubiquitination

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