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dc.contributor.authorHan, S-S
dc.contributor.authorWen, K-K
dc.contributor.authorGarcía-Rubio, ML
dc.contributor.authorWold, MS
dc.contributor.authorAguilera, A
dc.contributor.authorNiedzwiedz, W
dc.contributor.authorVyas, YM
dc.coverage.spatialEngland
dc.date.accessioned2022-09-14T10:55:24Z
dc.date.available2022-09-14T10:55:24Z
dc.date.issued2022-06-29
dc.identifierARTN 3743
dc.identifier10.1038/s41467-022-31415-z
dc.identifier.citationNature Communications, 2022, 13 (1), pp. 3743 -en_US
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5474
dc.identifier.eissn2041-1723
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/s41467-022-31415-z
dc.identifier.doi10.1038/s41467-022-31415-z
dc.description.abstractPerturbation in the replication-stress response (RSR) and DNA-damage response (DDR) causes genomic instability. Genomic instability occurs in Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency disorder, yet the mechanism remains largely uncharacterized. Replication protein A (RPA), a single-strand DNA (ssDNA) binding protein, has key roles in the RSR and DDR. Here we show that human WAS-protein (WASp) modulates RPA functions at perturbed replication forks (RFs). Following genotoxic insult, WASp accumulates at RFs, associates with RPA, and promotes RPA:ssDNA complexation. WASp deficiency in human lymphocytes destabilizes RPA:ssDNA-complexes, impairs accumulation of RPA, ATR, ETAA1, and TOPBP1 at genotoxin-perturbed RFs, decreases CHK1 activation, and provokes global RF dysfunction. las17 (yeast WAS-homolog)-deficient S. cerevisiae also show decreased ScRPA accumulation at perturbed RFs, impaired DNA recombination, and increased frequency of DNA double-strand break (DSB)-induced single-strand annealing (SSA). Consequently, WASp (or Las17)-deficient cells show increased frequency of DSBs upon genotoxic insult. Our study reveals an evolutionarily conserved, essential role of WASp in the DNA stress-resolution pathway, such that WASp deficiency provokes RPA dysfunction-coupled genomic instability.
dc.formatElectronic
dc.format.extent3743 -
dc.languageeng
dc.language.isoengen_US
dc.publisherNATURE PORTFOLIOen_US
dc.relation.ispartofNature Communications
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectAnimals
dc.subjectAntigens, Surface
dc.subjectDNA Breaks, Double-Stranded
dc.subjectDNA Repair
dc.subjectDNA Replication
dc.subjectDNA, Single-Stranded
dc.subjectDNA-Binding Proteins
dc.subjectGenomic Instability
dc.subjectHumans
dc.subjectProtein Binding
dc.subjectReplication Protein A
dc.subjectSaccharomyces cerevisiae
dc.subjectSaccharomyces cerevisiae Proteins
dc.subjectWiskott-Aldrich Syndrome Protein
dc.titleWASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage.en_US
dc.typeJournal Article
dcterms.dateAccepted2022-06-08
dc.date.updated2022-09-14T10:54:40Z
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1038/s41467-022-31415-zen_US
rioxxterms.licenseref.startdate2022-06-29
rioxxterms.typeJournal Article/Reviewen_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/35768435
pubs.issue1
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/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Cancer and Genome Instability
pubs.publication-statusPublished online
pubs.publisher-urlhttp://dx.doi.org/10.1038/s41467-022-31415-z
pubs.volume13
icr.researchteamCancer and Genome Instaben_US
dc.contributor.icrauthorNiedzwiedz, Wojciech
icr.provenanceDeposited by Mr Arek Surman on 2022-09-14. Deposit type is initial. No. of files: 1. Files: WASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage.pdf


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