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dc.contributor.authorPuddu, Fabioen
dc.contributor.authorSalguero, Ien
dc.contributor.authorHerzog, Mareikeen
dc.contributor.authorGeisler, NJen
dc.contributor.authorCostanzo, Ven
dc.contributor.authorJackson, Stephenen
dc.date.accessioned2017-05-26T13:14:17Z
dc.date.available2017-05-26T13:14:17Z
dc.date.issued2017-04-07en
dc.identifier.issn1469-221X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/264464
dc.description.abstractCamptothecin-induced locking of topoisomerase 1 on DNA generates a physical barrier to replication fork progression and creates topological stress. By allowing replisome rotation, absence of the Tof1/Csm3 complex promotes the conversion of impending topological stress to DNA catenation and causes camptothecin hypersensitivity. Through synthetic viability screening, we discovered that histone H4 K16 deacetylation drives the sensitivity of yeast cells to camptothecin and that inactivation of this pathway by mutating H4 K16 or the genes $\textit{SIR1-4}$ suppresses much of the hypersensitivity of $\textit{tof1}$∆ strains towards this agent. We show that disruption of rDNA or telomeric silencing does not mediate camptothecin resistance but that disruption of Sir1-dependent chromatin domains is sufficient to suppress camptothecin sensitivity in wild-type and $\textit{tof1}$∆ cells. We suggest that topoisomerase 1 inhibition in proximity of these domains causes topological stress that leads to DNA hypercatenation, especially in the absence of the Tof1/Csm3 complex. Finally, we provide evidence of the evolutionarily conservation of this mechanism.
dc.description.sponsorshipResearch in the Jackson laboratory is funded by Cancer Research UK [C6/A11224, C6/A18796, C6946/A14492] and the Wellcome Trust [WT092096]; FP was supported by the Associazione Italiana per la Ricerca sul Cancro [10932] and the European Molecular Biology Organization [ALTF1287-2011]; IS, MH, and NJG were supported by the Wellcome Trust [101126/Z/13/Z (Strategic Award—COMSIG)] and [098051 to MH]; VC is supported by the Armenise-Harvard Foundation and the Fondazione Telethon.
dc.languageengen
dc.language.isoenen
dc.publisherEMBO Press
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectH4‐K16en
dc.subjectSIR complexen
dc.subjectTof1en
dc.subjectcamptothecinen
dc.subjectsynthetic viabilityen
dc.titleChromatin determinants impart camptothecin sensitivityen
dc.typeArticle
prism.publicationDate2017en
prism.publicationNameEMBO Reportsen
dc.identifier.doi10.17863/CAM.9940
dcterms.dateAccepted2017-03-09en
rioxxterms.versionofrecord10.15252/embr.201643560en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-04-07en
dc.contributor.orcidPuddu, Fabio [0000-0002-2033-5209]
dc.contributor.orcidHerzog, Mareike [0000-0001-9747-2327]
dc.contributor.orcidJackson, Stephen [0000-0001-9317-7937]
dc.identifier.eissn1469-3178
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (A18796)
pubs.funder-project-idWellcome Trust (101126/Z/13/Z)
pubs.funder-project-idWellcome Trust (092096/Z/10/Z)
pubs.funder-project-idCancer Research UK (A14492)
cam.issuedOnline2017-04-07en
cam.orpheus.successThu Jan 30 12:53:57 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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