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dc.contributor.authorJohnson, Timothy I
dc.contributor.authorCosta, Ana SH
dc.contributor.authorFerguson, Ashley N
dc.contributor.authorFrezza, Christian
dc.date.accessioned2018-11-05T10:26:14Z
dc.date.available2018-11-05T10:26:14Z
dc.date.issued2018-09-06
dc.identifier.issn2041-4889
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284616
dc.description.abstractAn altered response to DNA damage is commonly associated with genomic instability, a hallmark of cancer. Fumarate hydratase (FH) was recently characterised as a DNA repair factor required in non-homologous end-joining (NHEJ) through the local production of fumarate. Inactivating germline mutations in FH cause hereditary leiomyomatosis and renal cell cancer (HLRCC), a cancer syndrome characterised by accumulation of fumarate. Recent data indicate that, in FH-deficient cells, fumarate suppresses homologous recombination DNA repair upon DNA double-strand breaks, compromising genome integrity. Here, we show that FH loss confers resistance to DNA damage caused by ionising radiation (IR), and promotes early mitotic entry after IR in a fumarate-specific manner, even in the presence of unrepaired damage, by suppressing checkpoint maintenance. We also showed that higher levels of DNA damage foci are detectable in untreated FH-deficient cells. Overall, these data indicate that FH loss and fumarate accumulation lead to a weakened G2 checkpoint that predisposes to endogenous DNA damage and confers resistance to IR.
dc.format.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectLeiomyomatosis
dc.subjectCarcinoma, Renal Cell
dc.subjectSkin Neoplasms
dc.subjectUterine Neoplasms
dc.subjectKidney Neoplasms
dc.subjectNeoplastic Syndromes, Hereditary
dc.subjectDNA Damage
dc.subjectGenomic Instability
dc.subjectFumarate Hydratase
dc.subjectMitosis
dc.subjectG2 Phase
dc.subjectDNA Repair
dc.subjectGerm-Line Mutation
dc.subjectRadiation, Ionizing
dc.titleFumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation.
dc.typeArticle
prism.issueIdentifier9
prism.publicationDate2018
prism.publicationNameCell Death Dis
prism.startingPage913
prism.volume9
dc.identifier.doi10.17863/CAM.31990
dcterms.dateAccepted2018-07-27
rioxxterms.versionofrecord10.1038/s41419-018-0912-3
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09-06
dc.contributor.orcidFrezza, Christian [0000-0002-3293-7397]
dc.identifier.eissn2041-4889
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMRC (unknown)
pubs.funder-project-idMedical Research Council (MC_UU_12022/6)
cam.issuedOnline2018-09-06


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International