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Article: ATM controls the extent of DNA end resection by eliciting sequential posttranslational modifications of CtIP

TitleATM controls the extent of DNA end resection by eliciting sequential posttranslational modifications of CtIP
Authors
KeywordsDNA end resection
homologous recombination
CtIP
ATM
hyperphosphorylation
Issue Date2021
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings of the National Academy of Sciences, 2021, v. 118 n. 12, p. article no. e2022600118 How to Cite?
AbstractDNA end resection is a critical step in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR). However, the mechanisms governing the extent of resection at DSB sites undergoing homology-directed repair remain unclear. Here, we show that, upon DSB induction, the key resection factor CtIP is modified by the ubiquitin-like protein SUMO at lysine 578 in a PIAS4-dependent manner. CtIP SUMOylation occurs on damaged chromatin and requires prior hyperphosphorylation by the ATM protein kinase. SUMO-modified hyperphosphorylated CtIP is targeted by the SUMO-dependent E3 ubiquitin ligase RNF4 for polyubiquitination and subsequent degradation. Consequently, disruption of CtIP SUMOylation results in aberrant accumulation of CtIP at DSBs, which, in turn, causes uncontrolled excessive resection, defective HR, and increased cellular sensitivity to DSB-inducing agents. These findings reveal a previously unidentified regulatory mechanism that regulates CtIP activity at DSBs and thus the extent of end resection via ATM-dependent sequential posttranslational modification of CtIP.
Persistent Identifierhttp://hdl.handle.net/10722/299297
ISSN
2020 Impact Factor: 11.205
2020 SCImago Journal Rankings: 5.011
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHan, J-
dc.contributor.authorWan, L-
dc.contributor.authorJiang, G-
dc.contributor.authorCao, L-
dc.contributor.authorXia, F-
dc.contributor.authorTian, T-
dc.contributor.authorZhu, X-
dc.contributor.authorWu, M-
dc.contributor.authorHuen, MSY-
dc.contributor.authorWang, Y-
dc.contributor.authorLiu, T-
dc.contributor.authorHuang, J-
dc.date.accessioned2021-05-10T06:59:48Z-
dc.date.available2021-05-10T06:59:48Z-
dc.date.issued2021-
dc.identifier.citationProceedings of the National Academy of Sciences, 2021, v. 118 n. 12, p. article no. e2022600118-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/299297-
dc.description.abstractDNA end resection is a critical step in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR). However, the mechanisms governing the extent of resection at DSB sites undergoing homology-directed repair remain unclear. Here, we show that, upon DSB induction, the key resection factor CtIP is modified by the ubiquitin-like protein SUMO at lysine 578 in a PIAS4-dependent manner. CtIP SUMOylation occurs on damaged chromatin and requires prior hyperphosphorylation by the ATM protein kinase. SUMO-modified hyperphosphorylated CtIP is targeted by the SUMO-dependent E3 ubiquitin ligase RNF4 for polyubiquitination and subsequent degradation. Consequently, disruption of CtIP SUMOylation results in aberrant accumulation of CtIP at DSBs, which, in turn, causes uncontrolled excessive resection, defective HR, and increased cellular sensitivity to DSB-inducing agents. These findings reveal a previously unidentified regulatory mechanism that regulates CtIP activity at DSBs and thus the extent of end resection via ATM-dependent sequential posttranslational modification of CtIP.-
dc.languageeng-
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org-
dc.relation.ispartofProceedings of the National Academy of Sciences-
dc.rightsProceedings of the National Academy of Sciences. Copyright © National Academy of Sciences.-
dc.subjectDNA end resection-
dc.subjecthomologous recombination-
dc.subjectCtIP-
dc.subjectATM-
dc.subjecthyperphosphorylation-
dc.titleATM controls the extent of DNA end resection by eliciting sequential posttranslational modifications of CtIP-
dc.typeArticle-
dc.identifier.emailHuen, MSY: huen.michael@hku.hk-
dc.identifier.authorityHuen, MSY=rp01336-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.2022600118-
dc.identifier.pmid33723063-
dc.identifier.pmcidPMC8000100-
dc.identifier.scopuseid_2-s2.0-85102718277-
dc.identifier.scopuseid_2-s2.0-85102718277-
dc.identifier.hkuros322434-
dc.identifier.volume118-
dc.identifier.issue12-
dc.identifier.spagearticle no. e2022600118-
dc.identifier.epagearticle no. e2022600118-
dc.identifier.isiWOS:000631868600060-
dc.publisher.placeUnited States-

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