Article

CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature

Department of Pharmacology, School of Medicine, University of California Irvine, Irvine 92697-4625, California, USA.
Nature (Impact Factor: 42.35). 01/2008; 450(7172):1086-90. DOI: 10.1038/nature06394
Source: PubMed

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.

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    • "Primary IP against Flag-SIRT1 revealed an interaction with CLOCK, and a secondary IP with HA-SIRT6 also revealed an interaction with CLOCK (Figure 4F), which is in keeping with evidence showing that these two sirtuins independently interact with the clock machinery. Lastly, SIRT1 has been shown to deacetylate BMAL1 at lysine 537 (Hirayama et al., 2007; Nakahata et al., 2008). Whereas SIRT1 readily deacetylates BMAL1, SIRT6 is not able to do so (Figure 4G), highlighting different mechanisms of action of these two sirtuins that reside in partitioned subcellular clock complexes. "
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    Cell 07/2014; 158(3):659-72. DOI:10.1016/j.cell.2014.06.050 · 33.12 Impact Factor
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    • "Interestingly, it was reported that CLOCK has an intrinsic histone acetyl transferase activity (HAT), reinforcing the idea of a link between the molecular circadian clock and epigenetic control [16]. CLOCK can acetylate non-histone proteins as well as its partner BMAL1 and the glucorticoid receptor [17] [18], supporting the notion that CLOCK is involved in establishing functional connections to a variety of metabolic pathways that impact the cell cycle and metabolic pathways [19]. "
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    07/2014; 5(3). DOI:10.14336/AD.2014.0500406
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    • "Other modifications also occur on core clock proteins. BMAL1, the mammalian ortholog of CYC, is acetylated by its partner, CLK, at the single lysine residue K572 with a timing corresponding to the repression phase of circadian transcription of clock-controlled genes (Hirayama et al. 2007; Nakahata et al. 2008). BMAL1 also exhibits a circadian pattern of sumoylation and ubiquitylation, which parallels its activation in mouse livers (Cardone et al. 2005; Lee et al. 2008); these dual modifications are essential for CLK/BMAL1 transcriptional activation. "
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