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Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD

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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.contributor.departmentFisiología
dc.date.accessioned2024-02-07T08:08:35Z
dc.date.available2024-02-07T08:08:35Z
dc.date.issued2021-02-18
dc.description©2020 The Author(s). This document is the Published version of a Published Work that appeared in final form in Molecular Cell. To access the final edited and published work see https://doi.org/10.1016/j.molcel.2020.12.006
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 attri- bute 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 em- ployed to augment existing therapeutic strategies for HRD cancers
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dc.format.extent29es
dc.identifier.citationMolecular Cell 81, 767–783, 2021
dc.identifier.doihttps://doi.org/10.1016/j.molcel.2020.12.006
dc.identifier.issnPrint: 1097-2765
dc.identifier.issnElectrónico: 1097-4164
dc.identifier.urihttp://hdl.handle.net/10201/138806
dc.languageenges
dc.publisherCell Presses
dc.relationWellcome Trust (grant number 210634), BBSRC (BB/R007195/1), and Cancer Research UK (C35050/A22284). Cancer Research UK Career Development Fellowship (grant number 16304). 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 Trust Senior Investigator and Collaborative Grants. EMBO Long Term Fellowship (ALTF 707-2019) and a MSCA individual fellowship (grant 886577). CRUK Career Development Fellowship (C52690/A19270), Wellcome core award 090532/Z/09/Z.es
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccess
dc.subject.otherCDU::5 - Ciencias puras y naturales::57 - Ciencias biológicas en general:577 - 577 Bioquímica. Biología molecular. Biofísica
dc.titleDefective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRDes
dc.typeinfo:eu-repo/semantics/articlees
dspace.entity.typePublicationes
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