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- Publisher Website: 10.1016/j.celrep.2024.114464
- Scopus: eid_2-s2.0-85198035612
- PMID: 38985669
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Article: FANCM promotes PARP inhibitor resistance by minimizing ssDNA gap formation and counteracting resection inhibition
Title | FANCM promotes PARP inhibitor resistance by minimizing ssDNA gap formation and counteracting resection inhibition |
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Authors | |
Keywords | 53BP1 CP: Molecular biology DNA end resection FANCM homologous recombination PARP inhibitor single-stranded DNA gap |
Issue Date | 23-Jul-2024 |
Publisher | Cell Press |
Citation | Cell Reports, 2024, v. 43, n. 7 How to Cite? |
Abstract | Poly(ADP-ribose) polymerase inhibitors (PARPis) exhibit remarkable anticancer activity in tumors with homologous recombination (HR) gene mutations. However, the role of other DNA repair proteins in PARPi-induced lethality remains elusive. Here, we reveal that FANCM promotes PARPi resistance independent of the core Fanconi anemia (FA) complex. FANCM-depleted cells retain HR proficiency, acting independently of BRCA1 in response to PARPis. FANCM depletion leads to increased DNA damage in the second S phase after PARPi exposure, driven by elevated single-strand DNA (ssDNA) gap formation behind replication forks in the first S phase. These gaps arise from both 53BP1- and primase and DNA directed polymerase (PRIMPOL)-dependent mechanisms. Notably, FANCM-depleted cells also exhibit reduced resection of collapsed forks, while 53BP1 deletion restores resection and mitigates PARPi sensitivity. Our results suggest that FANCM counteracts 53BP1 to repair PARPi-induced DNA damage. Furthermore, FANCM depletion leads to increased chromatin bridges and micronuclei formation after PARPi treatment, elucidating the mechanism underlying extensive cell death in FANCM-depleted cells. |
Persistent Identifier | http://hdl.handle.net/10722/345707 |
ISSN |
DC Field | Value | Language |
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dc.contributor.author | Liu, Zeyuan | - |
dc.contributor.author | Jiang, Huadong | - |
dc.contributor.author | Lee, Sze Yuen | - |
dc.contributor.author | Kong, Nannan | - |
dc.contributor.author | Chan, Ying Wai | - |
dc.date.accessioned | 2024-08-27T09:10:38Z | - |
dc.date.available | 2024-08-27T09:10:38Z | - |
dc.date.issued | 2024-07-23 | - |
dc.identifier.citation | Cell Reports, 2024, v. 43, n. 7 | - |
dc.identifier.issn | 2639-1856 | - |
dc.identifier.uri | http://hdl.handle.net/10722/345707 | - |
dc.description.abstract | <p>Poly(ADP-ribose) polymerase inhibitors (PARPis) exhibit remarkable anticancer activity in tumors with homologous recombination (HR) gene mutations. However, the role of other DNA repair proteins in PARPi-induced lethality remains elusive. Here, we reveal that FANCM promotes PARPi resistance independent of the core Fanconi anemia (FA) complex. FANCM-depleted cells retain HR proficiency, acting independently of BRCA1 in response to PARPis. FANCM depletion leads to increased DNA damage in the second S phase after PARPi exposure, driven by elevated single-strand DNA (ssDNA) gap formation behind replication forks in the first S phase. These gaps arise from both 53BP1- and primase and DNA directed polymerase (PRIMPOL)-dependent mechanisms. Notably, FANCM-depleted cells also exhibit reduced resection of collapsed forks, while 53BP1 deletion restores resection and mitigates PARPi sensitivity. Our results suggest that FANCM counteracts 53BP1 to repair PARPi-induced DNA damage. Furthermore, FANCM depletion leads to increased chromatin bridges and micronuclei formation after PARPi treatment, elucidating the mechanism underlying extensive cell death in FANCM-depleted cells.</p> | - |
dc.language | eng | - |
dc.publisher | Cell Press | - |
dc.relation.ispartof | Cell Reports | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | 53BP1 | - |
dc.subject | CP: Molecular biology | - |
dc.subject | DNA end resection | - |
dc.subject | FANCM | - |
dc.subject | homologous recombination | - |
dc.subject | PARP inhibitor | - |
dc.subject | single-stranded DNA gap | - |
dc.title | FANCM promotes PARP inhibitor resistance by minimizing ssDNA gap formation and counteracting resection inhibition | - |
dc.type | Article | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1016/j.celrep.2024.114464 | - |
dc.identifier.pmid | 38985669 | - |
dc.identifier.scopus | eid_2-s2.0-85198035612 | - |
dc.identifier.volume | 43 | - |
dc.identifier.issue | 7 | - |
dc.identifier.eissn | 2211-1247 | - |
dc.identifier.issnl | 2211-1247 | - |