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dc.contributor.authorMillan-Zambrano, Gonzalo
dc.contributor.authorSantos-Rosa, Helena
dc.contributor.authorPuddu, Fabio
dc.contributor.authorRobson, Samuel C
dc.contributor.authorJackson, Stephen P
dc.contributor.authorKouzarides, Tony
dc.date.accessioned2018-12-04T00:30:52Z
dc.date.available2018-12-04T00:30:52Z
dc.date.issued2018-11-15
dc.identifier.issn1097-2765
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286255
dc.description.abstractIn response to genotoxic stress, cells activate a signaling cascade known as the DNA damage checkpoint (DDC) that leads to a temporary cell cycle arrest and activation of DNA repair mechanisms. Because persistent DDC activation compromises cell viability, this process must be tightly regulated. However, despite its importance, the mechanisms regulating DDC recovery are not completely understood. Here, we identify a DNA-damage-regulated histone modification in Saccharomyces cerevisiae, phosphorylation of H4 threonine 80 (H4T80ph), and show that it triggers checkpoint inactivation. H4T80ph is critical for cell survival to DNA damage, and its absence causes impaired DDC recovery and persistent cell cycle arrest. We show that, in response to genotoxic stress, p21-activated kinase Cla4 phosphorylates H4T80 to recruit Rtt107 to sites of DNA damage. Rtt107 displaces the checkpoint adaptor Rad9, thereby interrupting the checkpoint-signaling cascade. Collectively, our results indicate that H4T80ph regulates DDC recovery.
dc.description.sponsorshipThe Kouzarides laboratory is supported by Cancer Research UK (grant reference RG17001). The Jackson laboratory is supported by Cancer Research UK (grant reference C6/A18796) and Wellcome Trust (Investigator Award 206388/Z/17/Z). Both laboratories benefit from core support from the Wellcome Trust (Core Grant reference WT203144) and Cancer Research UK (grant reference C6946/A24843). G.M.-Z. was funded by an EMBO long-term fellowship (ALTF907- 2014).
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectSaccharomyces cerevisiae
dc.subjectDNA Damage
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectIntracellular Signaling Peptides and Proteins
dc.subjectCell Cycle Proteins
dc.subjectSaccharomyces cerevisiae Proteins
dc.subjectNuclear Proteins
dc.subjectHistones
dc.subjectSignal Transduction
dc.subjectDNA Repair
dc.subjectProtein Binding
dc.subjectPhosphorylation
dc.subjectCell Cycle Checkpoints
dc.subjectCheckpoint Kinase 2
dc.titlePhosphorylation of Histone H4T80 Triggers DNA Damage Checkpoint Recovery.
dc.typeArticle
prism.endingPage635.e4
prism.issueIdentifier4
prism.publicationDate2018
prism.publicationNameMol Cell
prism.startingPage625
prism.volume72
dc.identifier.doi10.17863/CAM.33567
dcterms.dateAccepted2018-09-18
rioxxterms.versionofrecord10.1016/j.molcel.2018.09.023
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-11
dc.contributor.orcidPuddu, Fabio [0000-0002-2033-5209]
dc.contributor.orcidJackson, Stephen [0000-0001-9317-7937]
dc.contributor.orcidKouzarides, Tony [0000-0002-8918-4162]
dc.identifier.eissn1097-4164
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCancer Research UK (17001)
pubs.funder-project-idCancer Research UK (18796)
pubs.funder-project-idWellcome Trust (206388/Z/17/Z)
pubs.funder-project-idCancer Research UK (C6946/A24843)
pubs.funder-project-idWellcome Trust (203144/Z/16/Z)
cam.issuedOnline2018-10-25


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