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The integrated stress response induces R-loops and hinders replication fork progression

dc.contributor.authorChoo, Josephine Ann Mun Yee
dc.contributor.authorSchlösser, Denise
dc.contributor.authorManzini, Valentina
dc.contributor.authorMagerhans, Anna
dc.contributor.authorDobbelstein, Matthias
dc.date.accessioned2020-07-31T13:44:32Z
dc.date.available2020-07-31T13:44:32Z
dc.date.issued2020de
dc.identifier.urihttp://resolver.sub.uni-goettingen.de/purl?gs-1/17479
dc.description.abstractThe integrated stress response (ISR) allows cells to rapidly shutdown most of their protein synthesis in response to protein misfolding, amino acid deficiency, or virus infection. These stresses trigger the phosphorylation of the translation initiation factor eIF2alpha, which prevents the initiation of translation. Here we show that triggering the ISR drastically reduces the progression of DNA replication forks within 1 h, thus flanking the shutdown of protein synthesis with immediate inhibition of DNA synthesis. DNA replication is restored by compounds that inhibit eIF2alpha kinases or re-activate eIF2alpha. Mechanistically, the translational shutdown blocks histone synthesis, promoting the formation of DNA:RNA hybrids (R-loops), which interfere with DNA replication. R-loops accumulate upon histone depletion. Conversely, histone overexpression or R-loop removal by RNaseH1 each restores DNA replication in the context of ISR and histone depletion. In conclusion, the ISR rapidly stalls DNA synthesis through histone deficiency and R-loop formation. We propose that this shutdown mechanism prevents potentially detrimental DNA replication in the face of cellular stresses.de
dc.description.sponsorshipOpen-Access-Publikationsfonds 2020
dc.language.isoengde
dc.rightsopenAccess
dc.rightsNamensnennung 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectDNA; Tumour-suppressor proteinsde
dc.subject.ddc610
dc.titleThe integrated stress response induces R-loops and hinders replication fork progressionde
dc.typejournalArticlede
dc.identifier.doi10.1038/s41419-020-2727-2
dc.type.versionpublishedVersionde
dc.relation.eISSN2041-4889
dc.bibliographicCitation.volume11de
dc.bibliographicCitation.issue7de
dc.bibliographicCitation.firstPage1de
dc.bibliographicCitation.lastPage16de
dc.type.subtypejournalArticle
dc.bibliographicCitation.articlenumber538de
dc.description.statuspeerReviewedde
dc.bibliographicCitation.journalCell Death & Diseasede


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