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Feedback Regulation of Transcriptional Termination by the Mammalian Circadian Clock PERIOD Complex

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Science  03 Aug 2012:
Vol. 337, Issue 6094, pp. 599-602
DOI: 10.1126/science.1221592

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The Inner Workings of a Clock

Eukaryotic circadian clocks are built at least in part on transcriptional feedback loops, but the mechanisms underlying circadian feedback are poorly understood. Padmanabhan et al. (p. 599, published online 5 July) explored the transcriptional feedback mechanism at the heart of the mammalian circadian clock. The proteins PERIOD (PER) and CRYPTOCHROME suppress transcription of their own genes. PER complexes do so in part by recruiting a histone deacetylase to promoters of clock genes. But PER is also present on DNA in a complex with Senataxin, a helicase that functions in transcriptional termination. Senataxin appears to be inhibited in the PER complex, thus inhibiting termination and further reducing the rate of transcription.

Abstract

Eukaryotic circadian clocks are built on transcriptional feedback loops. In mammals, the PERIOD (PER) and CRYPTOCHROME (CRY) proteins accumulate, form a large nuclear complex (PER complex), and repress their own transcription. We found that mouse PER complexes included RNA helicases DDX5 and DHX9, active RNA polymerase II large subunit, Per and Cry pre-mRNAs, and SETX, a helicase that promotes transcriptional termination. During circadian negative feedback, RNA polymerase II accumulated near termination sites on Per and Cry genes but not on control genes. Recruitment of PER complexes to the elongating polymerase at Per and Cry termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. Circadian clock negative feedback thus includes direct control of transcriptional termination.

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