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dc.contributor.authorTakeda, Yukoen
dc.contributor.authorVenkitaraman, Ashoken
dc.date.accessioned2015-12-21T11:06:30Z
dc.date.available2015-12-21T11:06:30Z
dc.date.issued2015-06-25en
dc.identifier.citationCell Cycle 2015, 14(24): 3830-3841. doi:10.1080/15384101.2015.1064202en
dc.identifier.issn1538-4101
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/253057
dc.description.abstractThe DNA damage response (DDR) triggers widespread changes in gene expression, mediated partly by alterations in micro(mi) RNA levels, whose nature and significance remain uncertain. Here, we report that miR-34a, which is upregulated during the DDR, modulates the expression of protein phosphatase 1γ (PP1γ) to regulate cellular tolerance to DNA damage. Multiple bio-informatic algorithms predict that miR-34a targets the PP1CCC gene encoding PP1γ protein. Ionising radiation (IR) decreases cellular expression of PP1γ in a dose-dependent manner. An miR-34a-mimic reduces cellular PP1γ protein. Conversely, an miR-34a inhibitor antagonizes IR-induced decreases in PP1γ protein expression. A wild-type (but not mutant) miR-34a seed match sequence from the 3′ untranslated region (UTR) of PP1CCC when transplanted to a luciferase reporter gene makes it responsive to an miR-34a-mimic. Thus, miR-34a upregulation during the DDR targets the 3′ UTR of PP1CCC to decrease PP1γ protein expression. PP1γ is known to antagonize DDR signalling via the ataxia-telangiectasia-mutated (ATM) kinase. Interestingly, we find that cells exposed to DNA damage become more sensitive – in an miR-34a-dependent manner – to a second challenge with damage. Increased sensitivity to the second challenge is marked by enhanced phosphorylation of ATM and p53, increased γH2AX formation, and increased cell death. Increased sensitivity can be partly recapitulated by a miR-34a-mimic, or antagonized by an miR-34a-inhibitor. Thus, our findings suggest a model in which damage-induced miR-34a induction reduces PP1γ expression and enhances ATM signaling to decrease tolerance to repeated genotoxic challenges. This mechanism has implications for tumour suppression and the response of cancers to therapeutic radiation.
dc.description.sponsorshipWork in ARV's laboratory is funded by the Medical Research Council.
dc.languageEnglishen
dc.language.isoenen
dc.publisherTaylor & Francis
dc.rightsCreative Commons Attribution 4.0 International License
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleMicro(mi) RNA-34a targets protein phosphatase (PP)1γ to regulate DNA damage toleranceen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from Taylor & Francis via http://dx.doi.org/10.1080/15384101.2015.1064202en
prism.endingPage3841
prism.publicationDate2015en
prism.publicationNameCell Cycleen
prism.startingPage3830
prism.volume14en
dc.rioxxterms.funderMRC
rioxxterms.versionofrecord10.1080/15384101.2015.1064202en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-06-25en
dc.identifier.eissn1551-4005
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (G1001521)
pubs.funder-project-idMedical Research Council (MC_UU_12022/1)
pubs.funder-project-idMRC (MC_UU_12022/8)
pubs.funder-project-idMRC (MC_UU_12022/8)


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