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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    ABSTRACT: Circadian rhythms are intimately linked to cellular metabolism. Specifically, the NAD(+)-dependent deacetylase SIRT1, the founding member of the sirtuin family, contributes to clock function. Whereas SIRT1 exhibits diversity in deacetylation targets and subcellular localization, SIRT6 is the only constitutively chromatin-associated sirtuin and is prominently present at transcriptionally active genomic loci. Comparison of the hepatic circadian transcriptomes reveals that SIRT6 and SIRT1 separately control transcriptional specificity and therefore define distinctly partitioned classes of circadian genes. SIRT6 interacts with CLOCK:BMAL1 and, differently from SIRT1, governs their chromatin recruitment to circadian gene promoters. Moreover, SIRT6 controls circadian chromatin recruitment of SREBP-1, resulting in the cyclic regulation of genes implicated in fatty acid and cholesterol metabolism. This mechanism parallels a phenotypic disruption in fatty acid metabolism in SIRT6 null mice as revealed by circadian metabolome analyses. Thus, genomic partitioning by two independent sirtuins contributes to differential control of circadian metabolism.
    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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    ABSTRACT: Experimental findings and clinical observations have strengthened the association between physio-pathologic aspects of several diseases, as well as aging process, with the occurrence and control of circadian rhythms. The circadian system is composed by a principal pacemaker in the suprachiasmatic nucleus (SNC) which is in coordination with a number of peripheral circadian oscillators. Many pathological entities such as metabolic syndrome, cancer and cardiovascular events are strongly connected with a disruptive condition of the circadian cycle. Inadequate circadian physiology can be elicited by genetic defects (mutations in clock genes or circadian control genes) or physiological deficiencies (desynchronization between SCN and peripheral oscillators). In this review, we focus on the most recent experimental findings regarding molecular defects in the molecular circadian clock and the altered coordination in the circadian system that are related with clinical conditions such as metabolic diseases, cancer predisposition and physiological deficiencies associated to jet-lag and shiftwork schedules. Implications in the aging process will be also reviewed.
    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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    ABSTRACT: A conserved transcriptional feedback loop underlies animal circadian rhythms. In Drosophila, the transcription factors CLOCK (CLK) and CYCLE (CYC) activate the transcription of direct target genes like period (per) and timeless (tim). They encode the proteins PER and TIM, respectively, which repress CLK/CYC activity. Previous work indicates that repression is due to a direct PER-CLK/CYC interaction as well as CLK/CYC phosphorylation. We describe here the role of ubiquitin-specific protease 8 (USP8) in circadian transcriptional repression as well as the importance of CLK ubiquitylation in CLK/CYC transcription activity. usp8 loss of function (RNAi) or expression of a dominant-negative form of the protein (USP8-DN) enhances CLK/CYC transcriptional activity and alters fly locomotor activity rhythms. Clock protein and mRNA molecular oscillations are virtually absent within circadian neurons of USP8-DN flies. Furthermore, CLK ubiquitylation cycles robustly in wild-type flies and peaks coincident with maximal CLK/CYC transcription. As USP8 interacts with CLK and expression of USP8-DN increases CLK ubiquitylation, the data indicate that USP8 deubiquitylates CLK, which down-regulates CLK/CYC transcriptional activity. Taken together with the facts that usp8 mRNA cycles and that its transcription is activated directly by CLK/CYC, USP8, like PER and TIM, contributes to the transcriptional feedback loop cycle that underlies circadian rhythms.
    Genes & development 11/2012; 26(22):2536-49. DOI:10.1101/gad.200584.112 · 12.64 Impact Factor
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