The APE2 nuclease is essential for DNA double-strand break repair by microhomology-mediated end joining
Open accessPublished version of a preprint
Abstract
Microhomology-mediated end joining (MMEJ) is an intrinsically mutagenic pathway of DNA double-strand break (DSB) repair essential for proliferation of homologous recombination (HR)-deficient tumors. Although targeting MMEJ has emerged as a powerful strategy to eliminate HR-deficient (HRD) cancers, this is limited by an incomplete understanding of the mechanism and factors required for MMEJ repair. Here, we identify the APE2 nuclease as an MMEJ effector. We show that loss of APE2 inhibits MMEJ at deprotected telomeres and at intra-chromosomal DSBs and is epistatic with Pol Theta for MMEJ activity. Mechanistically, we demonstrate that APE2 possesses intrinsic flap-cleaving activity, that its MMEJ function in cells depends on its nuclease activity, and further identify an uncharacterized domain required for its recruitment to DSBs. We conclude that this previously unappreciated role of APE2 in MMEJ contributes to the addiction of HRD cells to APE2, which could be exploited in the treatment of cancer.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9
Doench, J. G., Fusi, N., Sullender, M., Hegde, M., Vaimberg, E. W., Donovan, K. F., Smith, I., Tothova, Z., Wilen, C., Orchard, R., et al. (2016) · Nature Biotechnology · doi:10.1038/nbt.3437 · Cited by 4,637 · see citing works
TRF2 Protects Human Telomeres from End-to-End Fusions
van Steensel, B., Smogorzewska, A., & de Lange, T. (1998) · Cell · doi:10.1016/s0092-8674(00)80932-0 · Cited by 1,709 · see citing works
DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion
Celli, G. B., & de Lange, T. (2005) · Nature Cell Biology · doi:10.1038/ncb1275 · Cited by 623 · see citing works
Pan-cancer landscape of homologous recombination deficiency.
Nguyen, L., W. M. Martens, J., Van Hoeck, A., & Cuppen, E. (2020) · Nature communications · doi:10.1038/s41467-020-19406-4 · Cited by 532 · see citing works
Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination
Tang, J., Cho, N. W., Cui, G., Manion, E. M., Shanbhag, N. M., Botuyan, M. V., Mer, G., & Greenberg, R. A. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2499 · Cited by 521 · see citing works
Celli, G. B., Denchi, E. L., & de Lange, T. (2006) · Nature Cell Biology · doi:10.1038/ncb1444 · Cited by 320 · see citing works
Adam, S., Rossi, S. E., Moatti, N., De Marco Zompit, M., Xue, Y., Ng, T. F., Álvarez-Quilón, A., Desjardins, J., Bhaskaran, V., Martino, G., et al. (2021) · Nature Cancer · doi:10.1038/s43018-021-00266-w · Cited by 121 · see citing works
Analysis of deletion breakpoints from 1,092 humans reveals details of mutation mechanisms
Abyzov, A., Li, S., Kim, D. R., Mohiyuddin, M., Stütz, A. M., Parrish, N. F., Mu, X. J., Clark, W., Chen, K., Hurles, M., et al. (2015) · Nature Communications · doi:10.1038/ncomms8256 · Cited by 91 · see citing works
Rare hereditary diseases with defects in DNA-repair
Knoch, J., Kamenisch, Y., Kubisch, C., & Berneburg, M. (2012) · European Journal of Dermatology · doi:10.1684/ejd.2012.1654 · Cited by 81 · see citing works
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- Authors
- Fleury, H., MacEachern, M. K., Stiefel, C. M., Anand, R., Sempeck, C., Nebenfuehr, B., Maurer-Alcalá, K., Ball, K., Proctor, B., Belan, O., Taylor, E., Ortega, R., Dodd, B., Weatherly, L., Dansoko, D., Leung, J. W., Boulton, S. J., & Arnoult, N.
- Affiliations
- University of Colorado Boulder (US)
- The University of Texas at San Antonio Health Science Center (US)
- The Francis Crick Institute (GB)
- Corresponding author
- Arnoult, Nausica
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2023-05
- Volume
- 83
- Issue
- 9
- Pages
- 1429-1445.e8
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC10164096
- OpenAlex
- W4364361542
- Cited by
- 52
- References
- 10
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 16 · 2023: 5
- FWCI
- 4.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research UK
- National Science Foundation (DGE2040434)
- European Research Council
- National Institutes of Health (R01CA244261, R01CA266100, R35GM137798, R35GM143108, T32GM008759, T32GM142607)
- Francis Crick Institute (cc2098)
- Philippe Foundation
- V Foundation for Cancer Research
- Glenn Foundation for Medical Research
- Boettcher Foundation
- Wellcome Trust
- American Cancer Society (RSG-20-131-01-DMC, TLC-21-164-01-TLC)
- American Federation for Aging Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- microhomology-mediated end joining, DNA double-strand break repair, homologous recombination deficiency, telomeres, nuclease activity
- MeSH terms
- DNA, DNA Repair, DNA Breaks, Double-Stranded, Homologous Recombination, DNA End-Joining Repair
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