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- Title
CLOCK-mediated acetylation of BMAL1 controls circadian function.
- Authors
Hirayama, Jun; Sahar, Saurabh; Grimaldi, Benedetto; Tamaru, Teruya; Takamatsu, Ken; Nakahata, Yasukazu; Sassone-Corsi, Paolo
- Abstract
Regulation of circadian physiology relies on the interplay of interconnected transcriptional-translational feedback loops. The CLOCK-BMAL1 complex activates clock-controlled genes, including cryptochromes (Crys), the products of which act as repressors by interacting directly with CLOCK-BMAL1. We have demonstrated that CLOCK possesses intrinsic histone acetyltransferase activity and that this enzymatic function contributes to chromatin-remodelling events implicated in circadian control of gene expression. Here we show that CLOCK also acetylates a non-histone substrate: its own partner, BMAL1, is specifically acetylated on a unique, highly conserved Lys 537 residue. BMAL1 undergoes rhythmic acetylation in mouse liver, with a timing that parallels the downregulation of circadian transcription of clock-controlled genes. BMAL1 acetylation facilitates recruitment of CRY1 to CLOCK-BMAL1, thereby promoting transcriptional repression. Importantly, ectopic expression of a K537R-mutated BMAL1 is not able to rescue circadian rhythmicity in a cellular model of peripheral clock. These findings reveal that the enzymatic interplay between two clock core components is crucial for the circadian machinery.
- Publication
Nature, 2007, Vol 450, Issue 7172, p1086
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature06394