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dc.contributor.authorNieminuszczy, Jen_US
dc.contributor.authorBroderick, Ren_US
dc.contributor.authorBellani, MAen_US
dc.contributor.authorSmethurst, Een_US
dc.contributor.authorSchwab, RAen_US
dc.contributor.authorCherdyntseva, Ven_US
dc.contributor.authorEvmorfopoulou, Ten_US
dc.contributor.authorLin, Y-Len_US
dc.contributor.authorMinczuk, Men_US
dc.contributor.authorPasero, Pen_US
dc.contributor.authorGagos, Sen_US
dc.contributor.authorSeidman, MMen_US
dc.contributor.authorNiedzwiedz, Wen_US
dc.date.accessioned2020-06-03T10:26:07Z
dc.date.issued2019-08
dc.identifier.citationMolecular cell, 2019, 75 (3), pp. 605 - 619.e6
dc.identifier.issn1097-2765
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3683
dc.identifier.eissn1097-4164
dc.identifier.doi10.1016/j.molcel.2019.05.026
dc.description.abstractAccurate DNA replication is essential to preserve genomic integrity and prevent chromosomal instability-associated diseases including cancer. Key to this process is the cells' ability to stabilize and restart stalled replication forks. Here, we show that the EXD2 nuclease is essential to this process. EXD2 recruitment to stressed forks suppresses their degradation by restraining excessive fork regression. Accordingly, EXD2 deficiency leads to fork collapse, hypersensitivity to replication inhibitors, and genomic instability. Impeding fork regression by inactivation of SMARCAL1 or removal of RECQ1's inhibition in EXD2<sup>-/-</sup> cells restores efficient fork restart and genome stability. Moreover, purified EXD2 efficiently processes substrates mimicking regressed forks. Thus, this work identifies a mechanism underpinned by EXD2's nuclease activity, by which cells balance fork regression with fork restoration to maintain genome stability. Interestingly, from a clinical perspective, we discover that EXD2's depletion is synthetic lethal with mutations in BRCA1/2, implying a non-redundant role in replication fork protection.en_US
dc.formatPrint-Electronic
dc.format.extent605 - 619.e6
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHela Cellsen_US
dc.subjectHumansen_US
dc.subjectNeoplasmsen_US
dc.subjectGenomic Instabilityen_US
dc.subjectExodeoxyribonucleasesen_US
dc.subjectDNA Helicasesen_US
dc.subjectBRCA1 Proteinen_US
dc.subjectBRCA2 Proteinen_US
dc.subjectDNA Replicationen_US
dc.subjectRecQ Helicasesen_US
dc.subjectSynthetic Lethal Mutationsen_US
dc.titleEXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2.
dc.typeJournal Article
dcterms.dateAccepted2019-05-17
rioxxterms.versionofrecord10.1016/j.molcel.2019.05.026
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-08
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular cellen_US
pubs.issue3
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/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Cancer and Genome Instability
pubs.publication-statusPublished
pubs.volume75en_US
pubs.embargo.termsNot known
icr.researchteamCancer and Genome Instabilityen_US
dc.contributor.icrauthorNiedzwiedz, Wojciechen


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