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dc.contributor.authorHewitt, G
dc.contributor.authorBorel, V
dc.contributor.authorSegura-Bayona, S
dc.contributor.authorTakaki, T
dc.contributor.authorRuis, P
dc.contributor.authorBellelli, R
dc.contributor.authorLehmann, LC
dc.contributor.authorSommerova, L
dc.contributor.authorVancevska, A
dc.contributor.authorTomas-Loba, A
dc.contributor.authorZhu, K
dc.contributor.authorCooper, C
dc.contributor.authorFugger, K
dc.contributor.authorPatel, H
dc.contributor.authorGoldstone, R
dc.contributor.authorSchneider-Luftman, D
dc.contributor.authorHerbert, E
dc.contributor.authorStamp, G
dc.contributor.authorBrough, R
dc.contributor.authorPettitt, S
dc.contributor.authorLord, CJ
dc.contributor.authorWest, SC
dc.contributor.authorAhel, I
dc.contributor.authorAhel, D
dc.contributor.authorChapman, JR
dc.contributor.authorDeindl, S
dc.contributor.authorBoulton, SJ
dc.date.accessioned2021-03-02T16:07:25Z
dc.date.available2021-03-02T16:07:25Z
dc.date.issued2020-12-15
dc.identifier.citationMolecular cell, 2020
dc.identifier.issn1097-2765
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4386
dc.identifier.eissn1097-4164
dc.identifier.doi10.1016/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 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.
dc.formatPrint-Electronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleDefective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.
dc.typeJournal Article
dcterms.dateAccepted2020-12-03
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/j.molcel.2020.12.006
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-12-15
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular cell
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.embargo.termsNot known
icr.researchteamGene Function
icr.researchteamGene Functionen_US
dc.contributor.icrauthorLord, Christopheren


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