FIRRM cooperates with FIGNL1 to promote RAD51 disassembly during DNA repair
Interstrand DNA cross-links (ICLs) represent complex lesions that compromise genomic stability. Several pathways have been involved in ICL repair, but the extent of factors involved in the resolution of ICL-induced DNA double-strand breaks (DSBs) remains poorly defined. Using CRISPR-based genomics,...
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| Veröffentlicht in: | Science advances 2023-08, Vol.9 (32), p.eadf4082-eadf4082 |
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| creator | Pinedo-Carpio, Edgar Dessapt, Julien Beneyton, Adèle Sacre, Lauralicia Bérubé, Marie-Anne Villot, Romain Lavoie, Elise G Coulombe, Yan Blondeau, Andréanne Boulais, Jonathan Malina, Abba Luo, Vincent M Lazaratos, Anna-Maria Côté, Jean-François Mallette, Frédérick A Guarné, Alba Masson, Jean-Yves Fradet-Turcotte, Amélie Orthwein, Alexandre |
| description | Interstrand DNA cross-links (ICLs) represent complex lesions that compromise genomic stability. Several pathways have been involved in ICL repair, but the extent of factors involved in the resolution of ICL-induced DNA double-strand breaks (DSBs) remains poorly defined. Using CRISPR-based genomics, we identified FIGNL1 interacting regulator of recombination and mitosis (FIRRM) as a sensitizer of the ICL-inducing agent mafosfamide. Mechanistically, we showed that FIRRM, like its interactor Fidgetin like 1 (FIGNL1), contributes to the resolution of RAD51 foci at ICL-induced DSBs. While the stability of FIGNL1 and FIRRM is interdependent, expression of a mutant of FIRRM (∆WCF), which stabilizes the protein in the absence of FIGNL1, allows the resolution of RAD51 foci and cell survival, suggesting that FIRRM has FIGNL1-independent function during DNA repair. In line with this model, FIRRM binds preferentially single-stranded DNA in vitro, raising the possibility that it directly contributes to RAD51 disassembly by interacting with DNA. Together, our findings establish FIRRM as a promoting factor of ICL repair. |
| doi_str_mv | 10.1126/sciadv.adf4082 |
| format | Article |
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Several pathways have been involved in ICL repair, but the extent of factors involved in the resolution of ICL-induced DNA double-strand breaks (DSBs) remains poorly defined. Using CRISPR-based genomics, we identified FIGNL1 interacting regulator of recombination and mitosis (FIRRM) as a sensitizer of the ICL-inducing agent mafosfamide. Mechanistically, we showed that FIRRM, like its interactor Fidgetin like 1 (FIGNL1), contributes to the resolution of RAD51 foci at ICL-induced DSBs. While the stability of FIGNL1 and FIRRM is interdependent, expression of a mutant of FIRRM (∆WCF), which stabilizes the protein in the absence of FIGNL1, allows the resolution of RAD51 foci and cell survival, suggesting that FIRRM has FIGNL1-independent function during DNA repair. In line with this model, FIRRM binds preferentially single-stranded DNA in vitro, raising the possibility that it directly contributes to RAD51 disassembly by interacting with DNA. Together, our findings establish FIRRM as a promoting factor of ICL repair.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.adf4082</identifier><identifier>PMID: 37556550</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Biomedicine and Life Sciences ; Cell Biology ; DNA - genetics ; DNA Repair ; Mitosis ; Molecular Biology ; Proteins - genetics ; Rad51 Recombinase - genetics ; Rad51 Recombinase - metabolism ; SciAdv r-articles</subject><ispartof>Science advances, 2023-08, Vol.9 (32), p.eadf4082-eadf4082</ispartof><rights>Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). 2023 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-af7d321b7e50bff231144d6daf5660f3d22ccbdf38efdaaa9ccdf2e673debb1c3</citedby><cites>FETCH-LOGICAL-c391t-af7d321b7e50bff231144d6daf5660f3d22ccbdf38efdaaa9ccdf2e673debb1c3</cites><orcidid>0009-0002-1159-1320 ; 0009-0009-2800-2837 ; 0000-0003-1848-0068 ; 0000-0002-8513-1186 ; 0000-0002-8511-9005 ; 0000-0001-7055-2642 ; 0000-0002-5431-8650 ; 0000-0003-4923-7159 ; 0000-0002-7350-3413 ; 0000-0002-3989-0261 ; 0000-0001-5748-3320 ; 0000-0001-7932-0338</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10411901/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10411901/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27922,27923,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37556550$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pinedo-Carpio, Edgar</creatorcontrib><creatorcontrib>Dessapt, Julien</creatorcontrib><creatorcontrib>Beneyton, Adèle</creatorcontrib><creatorcontrib>Sacre, Lauralicia</creatorcontrib><creatorcontrib>Bérubé, Marie-Anne</creatorcontrib><creatorcontrib>Villot, Romain</creatorcontrib><creatorcontrib>Lavoie, Elise G</creatorcontrib><creatorcontrib>Coulombe, Yan</creatorcontrib><creatorcontrib>Blondeau, Andréanne</creatorcontrib><creatorcontrib>Boulais, Jonathan</creatorcontrib><creatorcontrib>Malina, Abba</creatorcontrib><creatorcontrib>Luo, Vincent M</creatorcontrib><creatorcontrib>Lazaratos, Anna-Maria</creatorcontrib><creatorcontrib>Côté, Jean-François</creatorcontrib><creatorcontrib>Mallette, Frédérick A</creatorcontrib><creatorcontrib>Guarné, Alba</creatorcontrib><creatorcontrib>Masson, Jean-Yves</creatorcontrib><creatorcontrib>Fradet-Turcotte, Amélie</creatorcontrib><creatorcontrib>Orthwein, Alexandre</creatorcontrib><title>FIRRM cooperates with FIGNL1 to promote RAD51 disassembly during DNA repair</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>Interstrand DNA cross-links (ICLs) represent complex lesions that compromise genomic stability. Several pathways have been involved in ICL repair, but the extent of factors involved in the resolution of ICL-induced DNA double-strand breaks (DSBs) remains poorly defined. Using CRISPR-based genomics, we identified FIGNL1 interacting regulator of recombination and mitosis (FIRRM) as a sensitizer of the ICL-inducing agent mafosfamide. Mechanistically, we showed that FIRRM, like its interactor Fidgetin like 1 (FIGNL1), contributes to the resolution of RAD51 foci at ICL-induced DSBs. While the stability of FIGNL1 and FIRRM is interdependent, expression of a mutant of FIRRM (∆WCF), which stabilizes the protein in the absence of FIGNL1, allows the resolution of RAD51 foci and cell survival, suggesting that FIRRM has FIGNL1-independent function during DNA repair. In line with this model, FIRRM binds preferentially single-stranded DNA in vitro, raising the possibility that it directly contributes to RAD51 disassembly by interacting with DNA. Together, our findings establish FIRRM as a promoting factor of ICL repair.</description><subject>Biomedicine and Life Sciences</subject><subject>Cell Biology</subject><subject>DNA - genetics</subject><subject>DNA Repair</subject><subject>Mitosis</subject><subject>Molecular Biology</subject><subject>Proteins - genetics</subject><subject>Rad51 Recombinase - genetics</subject><subject>Rad51 Recombinase - metabolism</subject><subject>SciAdv r-articles</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1PAjEQxRujEYJcPZoevYCddrssJ0NAkIiYED033X5AzS5d2wXDfy8GJHiaSd6b30zmIXQLpAtA04eonNTbrtQ2IRm9QE3KerxDeZJdnvUN1I7xkxACSZpy6F-jxl7iKeekiV7G08XiFSvvKxNkbSL-dvUKj6eT-Qxw7XEVfOlrgxeDEQesXZQxmjIvdlhvglsv8Wg-wMFU0oUbdGVlEU37WFvoY_z0PnzuzN4m0-Fg1lGsD3VH2p5mFPKe4SS3ljKAJNGplpanKbFMU6pUri3LjNVSyr5S2lKT9pg2eQ6KtdDjgVtt8tJoZdZ1kIWogitl2AkvnfivrN1KLP1WAEkA-gT2hPsjIfivjYm1KF1Upijk2vhNFDRLsixhjGd7a_dgVcHHGIw97QEiflMQhxTEMYX9wN35dSf738_ZD8knhf8</recordid><startdate>20230809</startdate><enddate>20230809</enddate><creator>Pinedo-Carpio, Edgar</creator><creator>Dessapt, Julien</creator><creator>Beneyton, Adèle</creator><creator>Sacre, Lauralicia</creator><creator>Bérubé, Marie-Anne</creator><creator>Villot, Romain</creator><creator>Lavoie, Elise G</creator><creator>Coulombe, Yan</creator><creator>Blondeau, Andréanne</creator><creator>Boulais, Jonathan</creator><creator>Malina, Abba</creator><creator>Luo, Vincent M</creator><creator>Lazaratos, Anna-Maria</creator><creator>Côté, Jean-François</creator><creator>Mallette, Frédérick A</creator><creator>Guarné, Alba</creator><creator>Masson, Jean-Yves</creator><creator>Fradet-Turcotte, Amélie</creator><creator>Orthwein, Alexandre</creator><general>American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0009-0002-1159-1320</orcidid><orcidid>https://orcid.org/0009-0009-2800-2837</orcidid><orcidid>https://orcid.org/0000-0003-1848-0068</orcidid><orcidid>https://orcid.org/0000-0002-8513-1186</orcidid><orcidid>https://orcid.org/0000-0002-8511-9005</orcidid><orcidid>https://orcid.org/0000-0001-7055-2642</orcidid><orcidid>https://orcid.org/0000-0002-5431-8650</orcidid><orcidid>https://orcid.org/0000-0003-4923-7159</orcidid><orcidid>https://orcid.org/0000-0002-7350-3413</orcidid><orcidid>https://orcid.org/0000-0002-3989-0261</orcidid><orcidid>https://orcid.org/0000-0001-5748-3320</orcidid><orcidid>https://orcid.org/0000-0001-7932-0338</orcidid></search><sort><creationdate>20230809</creationdate><title>FIRRM cooperates with FIGNL1 to promote RAD51 disassembly during DNA repair</title><author>Pinedo-Carpio, Edgar ; Dessapt, Julien ; Beneyton, Adèle ; Sacre, Lauralicia ; Bérubé, Marie-Anne ; Villot, Romain ; Lavoie, Elise G ; Coulombe, Yan ; Blondeau, Andréanne ; Boulais, Jonathan ; Malina, Abba ; Luo, Vincent M ; Lazaratos, Anna-Maria ; Côté, Jean-François ; Mallette, Frédérick A ; Guarné, Alba ; Masson, Jean-Yves ; Fradet-Turcotte, Amélie ; Orthwein, Alexandre</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-af7d321b7e50bff231144d6daf5660f3d22ccbdf38efdaaa9ccdf2e673debb1c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Biomedicine and Life Sciences</topic><topic>Cell Biology</topic><topic>DNA - genetics</topic><topic>DNA Repair</topic><topic>Mitosis</topic><topic>Molecular Biology</topic><topic>Proteins - genetics</topic><topic>Rad51 Recombinase - genetics</topic><topic>Rad51 Recombinase - metabolism</topic><topic>SciAdv r-articles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pinedo-Carpio, Edgar</creatorcontrib><creatorcontrib>Dessapt, Julien</creatorcontrib><creatorcontrib>Beneyton, Adèle</creatorcontrib><creatorcontrib>Sacre, Lauralicia</creatorcontrib><creatorcontrib>Bérubé, Marie-Anne</creatorcontrib><creatorcontrib>Villot, Romain</creatorcontrib><creatorcontrib>Lavoie, Elise G</creatorcontrib><creatorcontrib>Coulombe, Yan</creatorcontrib><creatorcontrib>Blondeau, Andréanne</creatorcontrib><creatorcontrib>Boulais, Jonathan</creatorcontrib><creatorcontrib>Malina, Abba</creatorcontrib><creatorcontrib>Luo, Vincent M</creatorcontrib><creatorcontrib>Lazaratos, Anna-Maria</creatorcontrib><creatorcontrib>Côté, Jean-François</creatorcontrib><creatorcontrib>Mallette, Frédérick A</creatorcontrib><creatorcontrib>Guarné, Alba</creatorcontrib><creatorcontrib>Masson, Jean-Yves</creatorcontrib><creatorcontrib>Fradet-Turcotte, Amélie</creatorcontrib><creatorcontrib>Orthwein, Alexandre</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pinedo-Carpio, Edgar</au><au>Dessapt, Julien</au><au>Beneyton, Adèle</au><au>Sacre, Lauralicia</au><au>Bérubé, Marie-Anne</au><au>Villot, Romain</au><au>Lavoie, Elise G</au><au>Coulombe, Yan</au><au>Blondeau, Andréanne</au><au>Boulais, Jonathan</au><au>Malina, Abba</au><au>Luo, Vincent M</au><au>Lazaratos, Anna-Maria</au><au>Côté, Jean-François</au><au>Mallette, Frédérick A</au><au>Guarné, Alba</au><au>Masson, Jean-Yves</au><au>Fradet-Turcotte, Amélie</au><au>Orthwein, Alexandre</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FIRRM cooperates with FIGNL1 to promote RAD51 disassembly during DNA repair</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2023-08-09</date><risdate>2023</risdate><volume>9</volume><issue>32</issue><spage>eadf4082</spage><epage>eadf4082</epage><pages>eadf4082-eadf4082</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>Interstrand DNA cross-links (ICLs) represent complex lesions that compromise genomic stability. Several pathways have been involved in ICL repair, but the extent of factors involved in the resolution of ICL-induced DNA double-strand breaks (DSBs) remains poorly defined. Using CRISPR-based genomics, we identified FIGNL1 interacting regulator of recombination and mitosis (FIRRM) as a sensitizer of the ICL-inducing agent mafosfamide. Mechanistically, we showed that FIRRM, like its interactor Fidgetin like 1 (FIGNL1), contributes to the resolution of RAD51 foci at ICL-induced DSBs. While the stability of FIGNL1 and FIRRM is interdependent, expression of a mutant of FIRRM (∆WCF), which stabilizes the protein in the absence of FIGNL1, allows the resolution of RAD51 foci and cell survival, suggesting that FIRRM has FIGNL1-independent function during DNA repair. In line with this model, FIRRM binds preferentially single-stranded DNA in vitro, raising the possibility that it directly contributes to RAD51 disassembly by interacting with DNA. 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| ispartof | Science advances, 2023-08, Vol.9 (32), p.eadf4082-eadf4082 |
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| source | MEDLINE; Directory of Open Journals (DOAJ); EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Biomedicine and Life Sciences Cell Biology DNA - genetics DNA Repair Mitosis Molecular Biology Proteins - genetics Rad51 Recombinase - genetics Rad51 Recombinase - metabolism SciAdv r-articles |
| title | FIRRM cooperates with FIGNL1 to promote RAD51 disassembly during DNA repair |
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