dc.contributor.author | Han, S-S | |
dc.contributor.author | Wen, K-K | |
dc.contributor.author | García-Rubio, ML | |
dc.contributor.author | Wold, MS | |
dc.contributor.author | Aguilera, A | |
dc.contributor.author | Niedzwiedz, W | |
dc.contributor.author | Vyas, YM | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2022-09-14T10:55:24Z | |
dc.date.available | 2022-09-14T10:55:24Z | |
dc.date.issued | 2022-06-29 | |
dc.identifier | ARTN 3743 | |
dc.identifier | 10.1038/s41467-022-31415-z | |
dc.identifier.citation | Nature Communications, 2022, 13 (1), pp. 3743 - | en_US |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5474 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/s41467-022-31415-z | |
dc.description.abstract | Perturbation 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.format | Electronic | |
dc.format.extent | 3743 - | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | NATURE PORTFOLIO | en_US |
dc.relation.ispartof | Nature Communications | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Animals | |
dc.subject | Antigens, Surface | |
dc.subject | DNA Breaks, Double-Stranded | |
dc.subject | DNA Repair | |
dc.subject | DNA Replication | |
dc.subject | DNA, Single-Stranded | |
dc.subject | DNA-Binding Proteins | |
dc.subject | Genomic Instability | |
dc.subject | Humans | |
dc.subject | Protein Binding | |
dc.subject | Replication Protein A | |
dc.subject | Saccharomyces cerevisiae | |
dc.subject | Saccharomyces cerevisiae Proteins | |
dc.subject | Wiskott-Aldrich Syndrome Protein | |
dc.title | WASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2022-06-08 | |
dc.date.updated | 2022-09-14T10:54:40Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1038/s41467-022-31415-z | en_US |
rioxxterms.licenseref.startdate | 2022-06-29 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/35768435 | |
pubs.issue | 1 | |
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-status | Published online | |
pubs.publisher-url | http://dx.doi.org/10.1038/s41467-022-31415-z | |
pubs.volume | 13 | |
icr.researchteam | Cancer and Genome Instab | en_US |
dc.contributor.icrauthor | Niedzwiedz, Wojciech | |
icr.provenance | Deposited 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 | |