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dc.contributor.authorNieminuszczy, J
dc.contributor.authorBroderick, R
dc.contributor.authorBellani, MA
dc.contributor.authorSmethurst, E
dc.contributor.authorSchwab, RA
dc.contributor.authorCherdyntseva, V
dc.contributor.authorEvmorfopoulou, T
dc.contributor.authorLin, Y-L
dc.contributor.authorMinczuk, M
dc.contributor.authorPasero, P
dc.contributor.authorGagos, S
dc.contributor.authorSeidman, MM
dc.contributor.authorNiedzwiedz, W
dc.date.accessioned2020-06-03T10:26:07Z
dc.date.issued2019-08-08
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-/- 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.
dc.formatPrint-Electronic
dc.format.extent605 - 619.e6
dc.languageeng
dc.language.isoeng
dc.publisherCELL PRESS
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHela Cells
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectGenomic Instability
dc.subjectExodeoxyribonucleases
dc.subjectDNA Helicases
dc.subjectBRCA1 Protein
dc.subjectBRCA2 Protein
dc.subjectDNA Replication
dc.subjectRecQ Helicases
dc.subjectSynthetic Lethal Mutations
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 cell
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.volume75
pubs.embargo.termsNot known
icr.researchteamCancer and Genome Instability
dc.contributor.icrauthorNiedzwiedz, Wojciech


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