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dc.contributor.authorHewitt, Graeme
dc.contributor.authorBorel, Valerie
dc.contributor.authorSegura-Bayona, Sandra
dc.contributor.authorTakaki, Tohru
dc.contributor.authorRuis, Phil
dc.contributor.authorBellelli, Roberto
dc.contributor.authorLehmann, Laura C
dc.contributor.authorSommerova, Lucia
dc.contributor.authorVancevska, Aleksandra
dc.contributor.authorTomas-Loba, Antonia 
dc.contributor.authorZhu, Kang
dc.contributor.authorCooper, Christopher
dc.contributor.authorFugger, Kasper
dc.contributor.authorPatel, Harshil
dc.contributor.authorGoldstone, Robert
dc.contributor.authorSchneider-Luftman, Deborah
dc.contributor.authorHerbert, Ellie
dc.contributor.authorStamp, Gordon
dc.contributor.authorBrough, Rachel
dc.contributor.authorPettitt, Stephen
dc.contributor.authorLord, Christopher J
dc.contributor.authorWest, Stephen C
dc.contributor.authorAhel, Ivan
dc.contributor.authorAhel, Dragana
dc.contributor.authorChapman, J Ross
dc.contributor.authorDeindl, Sebastian
dc.contributor.authorBoulton, Simon J
dc.date.accessioned2021-09-02T09:49:08Z
dc.date.available2021-09-02T09:49:08Z
dc.date.issued2021-02
dc.identifier.citationMol Cell. 2021; 81:767-783.e11es_ES
dc.identifier.issn1097-2765es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/13347
dc.description.abstractChromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1. Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks. In the absence of ALC1 or APEX1, incomplete processing of BER intermediates results in post-replicative DNA gaps and a critical dependence on HR for repair. Hence, targeting ALC1 alone or as a PARP inhibitor sensitizer could be employed to augment existing therapeutic strategies for HRD cancers.es_ES
dc.description.sponsorshipWork in I.A.’s group is funded by the WellcomeTrust (grant number 210634), BBSRC (BB/R007195/1), and Cancer ResearchUK (C35050/A22284). Work in D.A.’s group is funded by the Cancer ResearchUK Career Development Fellowship (grant number 16304). Work in the S.J.B.lab is supported by the Coun, which receives its core fundingfrom Cancer Research UK (FC0010048), the UK Medical Research Council(FC0010048), and the Wellcome Trust (FC0010048); a European Research Council (ERC) Advanced Investigator Grant (TelMetab); and Wellcome TrustSenior Investigator and Collaborative Grants. S.S.-B. was the recipient of an EMBO Long Term Fellowship (ALTF 707-2019) and a MSCA individual fellow-ship (grant 886577). Work in the J.R.C. group is funded by CRUK Career Devel-opment Fellowship (C52690/A19270) with infrastructural support from Well-come core award 090532/Z/09/Zes_ES
dc.language.isoenges_ES
dc.publisherCell Press es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subject.meshChromatin Assembly and Disassembly es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshDNA Helicases es_ES
dc.subject.meshDNA Replication es_ES
dc.subject.meshDNA-(Apurinic or Apyrimidinic Site) Lyase es_ES
dc.subject.meshDNA-Binding Proteins es_ES
dc.subject.meshHomologous Recombination es_ES
dc.subject.meshMice es_ES
dc.subject.meshMice, Knockout es_ES
dc.subject.meshNeoplasm Proteins es_ES
dc.subject.meshNeoplasms, Experimental es_ES
dc.subject.meshNucleosomes es_ES
dc.subject.meshPoly(ADP-ribose) Polymerase Inhibitors es_ES
dc.subject.meshPoly(ADP-ribose) Polymerases es_ES
dc.titleDefective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.es_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID33333017es_ES
dc.format.volume81es_ES
dc.format.number4es_ES
dc.format.page767-783.e11es_ES
dc.identifier.doi10.1016/j.molcel.2020.12.006es_ES
dc.contributor.funderWellcome Trust 
dc.contributor.funderCancer Research UK (Reino Unido) 
dc.contributor.funderThe Francis Crick Institute 
dc.contributor.funderMedical Research Council (Reino Unido) 
dc.contributor.funderEuropean Molecular Biology Organization 
dc.contributor.funderUnión Europea. Comisión Europea 
dc.description.peerreviewedes_ES
dc.identifier.e-issn1097-4164es_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.molcel.2020.12.006es_ES
dc.identifier.journalMolecular celles_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Antiguos CNICes_ES
dc.repisalud.institucionCNICes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/886577es_ES
dc.rights.accessRightsopen accesses_ES


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