Association of the circadian factor Period 2 to p53 influences p53’s function in DNA-damage signaling

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dc.contributor.authorGotoh, Testuyaen
dc.contributor.authorVila-Caballer, Marianen
dc.contributor.authorLiu, Jingjingen
dc.contributor.authorSchifhauer, Samuelen
dc.contributor.authorFinkielstein, Carla V.en
dc.contributor.departmentBiological Sciencesen
dc.date.accessioned2019-06-26T13:08:43Zen
dc.date.available2019-06-26T13:08:43Zen
dc.date.issued2014-11-19en
dc.description.abstractCircadian period proteins influence cell division and death by associating with checkpoint components, although their mode of regulation has not been firmly established. hPer2 forms a trimeric complex with hp53 and its negative regulator Mdm2. In unstressed cells, this association leads to increased hp53 stability by blocking Mdm2-dependent ubiquitination and transcription of hp53 target genes. Because of the relevance of hp53 in checkpoint signaling, we hypothesize that hPer2 association with hp53 acts as a regulatory module that influences hp53’s downstream response to genotoxic stress. Unlike the trimeric complex, whose distribution was confined to the nuclear compartment, hPer2/hp53 was identified in both cytosol and nucleus. At the transcriptional level, a reporter containing the hp21WAF1/CIP1 promoter, a target of hp53, remained inactive in cells expressing a stable form of the hPer2/hp53 complex even when treated with γ-radiation. Finally, we established that hPer2 directly acts on the hp53 node, as checkpoint components upstream of hp53 remained active in response to DNA damage. Quantitative transcriptional analyses of hp53 target genes demonstrated that unbound hp53 was absolutely required for activation of the DNA-damage response. Our results provide evidence of the mode by which the circadian tumor suppressor hPer2 modulates hp53 signaling in response to genotoxic stress.en
dc.description.sponsorshipThis work was supported by a National Science Foundation CAREER Award (MCB-0844491), the Avon Foundation (02-2009-033), the Fralin Life Science Institute (F441598), and the Susan G. Komen Foundation (BCTR0706931) to C.V.F.en
dc.identifier.doihttps://doi.org/10.1091/mbc.e14-05-0994en
dc.identifier.urihttp://hdl.handle.net/10919/90662en
dc.identifier.volume26en
dc.language.isoenen
dc.publisherAmerican Society for Cell Biologyen
dc.rightsCreative Commons Attribution-NonCommercial-ShareAlike 3.0 Unporteden
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/en
dc.titleAssociation of the circadian factor Period 2 to p53 influences p53’s function in DNA-damage signalingen
dc.title.serialMolecular Biology of the Cellen
dc.typeArticle - Refereeden

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