Gotoh T, Vila-Caballer M, Santos CS, Liu J, Yang J, Finkielstein CV

Period 2 (hPer2) is a transcriptional regulator placed at the core of the circadian clock mechanism that is responsible for generating the negative feedback loop that sustains the clock. Its relevance to human disease is underlined by alterations in its function that impacts numerous biochemical and physiological processes. When absent, ...

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it results in the development of various cancers and an increase in the cell's susceptibility to genotoxic stress. Thus, we aim to define a yet uncharacterized checkpoint node in which circadian components integrate environmental stress signals to the DNA-damage response. Accordingly, we found that hPer2 binds the C-terminus half of human p53 (hp53) and forms a stable trimeric complex together with hp53's negative regulator Mdm2. We determined that hPer2 binding to hp53 prevents Mdm2 from being ubiquitinated and targeting hp53 by the proteasome. Accordingly, down-regulation of hPer2 expression directly impacts hp53 levels whereas its overexpression influences both hp53 protein stability and transcription of targeted genes. Overall, our findings place hPer2 directly at the heart of the hp53-mediated response by ensuring that basal levels of hp53 are available to precondition the cell when a rapid, hp53-mediated, transcriptional response is needed.

Date: Aug. 07, 2014

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