CK2α phosphorylates BMAL1 to regulate the mammalian clock

Tamaru, Teruya; Hirayama, Jun; Isojima, Yasushi; Nonomura, Katsuya; Norioka, Shigemi; Takamatsu, Ken; Sassone–Corsi, Paolo

doi:10.1038/nsmb.1578

Cited by 120 publications

(124 citation statements)

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“…It has been reported that three of the four serine residues (CLOCK Ser38, Ser42 and BMAL1 Ser90) can Table S1 for full-length DNA used in ITC measurements. be phosphorylated in vivo [38,39]. However, BMAL1 Ser78 is also very likely to undergo phosphorylation predicted by NetPhos 2.0 Server [40], which is supported by the finding of a mass spectrometry record of phosphorylated BMAL1 Ser78 in PhosphoSite database [41].…”

Section: Potential Phosphorylation Sites In Basic Regionssupporting

confidence: 48%

Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA

Wang

et al. 2012

Cell Res

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CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle ARNT-like 1) are both transcription factors of the circadian core loop in mammals. Recently published mouse CLOCK-BMAL1 bHLH (basic helix-loop-helix)-PAS (period-ARNT-single-minded) complex structure sheds light on the mechanism for heterodimer formation, but the structural details of the protein-DNA recognition mechanisms remain elusive. Here we have elucidated the crystal structure of human CLOCK-BMAL1 bHLH domains bound to a canonical E-box DNA. We demonstrate that CLOCK and BMAL1 bHLH domains can be mutually selected, and that hydrogen-bonding networks mediate their E-box recognition. We identified a hydrophobic contact between BMAL1 Ile80 and a flanking thymine nucleotide, suggesting that CLOCK-BMAL1 actually reads 7-bp DNA and not the previously believed 6-bp DNA. To find potential non-canonical E-boxes that could be recognized by CLOCK-BMAL1, we constructed systematic single-nucleotide mutations on the E-box and measured their relevant affinities. We defined two non-canonical E-box patterns with high affinities, AACGTGA and CATGTGA, in which the flanking A7-T7′ base pair is indispensable for recognition. These results will help us to identify functional CLOCK-BMAL1-binding sites in vivo and to search for clock-controlled genes. Furthermore, we assessed the inhibitory role of potential phosphorylation sites in bHLH regions. We found that the phospho-mimicking mutation on BMAL1 Ser78 could efficiently block DNA binding as well as abolish normal circadian oscillation in cells. We propose that BMAL1 Ser78 should be a key residue mediating input signal-regulated transcriptional inhibition for external cues to entrain the circadian clock by kinase cascade.

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Section: Potential Phosphorylation Sites In Basic Regionssupporting

confidence: 48%

Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA

Wang

et al. 2012

Cell Res

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“…Most of the proposed targets of the 10 potent compounds on the list in Table S3 have not been identified as components of the mammalian circadian clock, although one of the 10 is an inhibitor of CK2, recently found as a component of the mammalian circadian clock (29,30). The potent protein kinase inhibitors SB202190, SP600125, and roscovitine were previously reported to inhibit CKI in addition to their primary targets (31,32).…”

Section: Resultsmentioning

confidence: 99%

CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock

Isojima

Nakajima

Ukai

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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T he circadian clock is a molecular mechanism underlying endogenous, self-sustained oscillations with a period of Ϸ24 h, manifested in diverse physiological and metabolic processes (1-3). The most striking feature of circadian clock is its flexible yet robust response to various environmental conditions. For example, circadian periodicity varies with light intensity (4-6) while remaining robust over a wide range of temperatures (''temperature compensation'') (1, 3, 7-9). This flexible-yetrobust characteristic is evolutionarily conserved in organisms ranging from photosynthetic bacteria to warm-blooded mammals (3, 10-12), and has interested researchers from a broad range of disciplines. However, despite many genetic and molecular studies (13-22), the detailed biochemical mechanism underlying this characteristic remains poorly elucidated (3).The simplest explanation for this flexible-yet-robust property is that the key period-determining reactions are insensitive to temperature but responsive to other environmental conditions. Indeed, Pittendrigh proposed the existence of a temperatureinsensitive component in the clock system in 1954 (7), and in 1968, he and his colleagues demonstrated that both the wave form and the period of circadian oscillations are invariant with temperature (23). However, the idea of a temperatureinsensitive biochemical reaction is counterintuitive, as elementary chemical processes are highly temperature-sensitive. One exception is the cyanobacterial clock, in which temperatureinsensitive enzymatic reactions are observed (24,25). However, the cyanobacterial clock is quite distinct from other clock systems, and this biochemical mechanism has not been demonstrated in other clocks.Recently, a chemical-biological approach was proposed to help elucidate the basic processes underlying circadian clocks (26), and high-throughput screening of a large chemical compound library was performed (27). In this report, to analyze systematically the fundamental processes involved in determining the period length of mammalian clocks, we tested 1,260 pharmacologically active compounds for their effect on period length in mouse and human clock cell lines, and found 10 compounds that most markedly lengthened the period of both clock cell lines affected both the central and peripheral circadian clocks. Most compounds inhibited CKI or CKI␦ activity, suggesting that CKI /␦-dependent phosphorylation is an important period-determining process in the mammalian circadian clock. Surprisingly, the degradation rate of endogenous PER2, which is regulated by CKI -dependent phosphorylation (28) and probably by CKI␦-dependent phosphorylation, was temperatureinsensitive in the living clock cells, and the temperatureinsensitivity was preserved even for the in vitro CKI /␦-dependent phosphorylation of a synthetic peptide derived from PER2. These results suggest that this period-determining process is flexible in response to chemical perturbation yet robust in the face of temperature perturbations. Based on these findings, we prop...

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“…An important site of CK2 activity is the serine residue at position 90 (S90) in BMAL1, the mutation of which leads to disruptions in circadian rhythmicity (Tamaru et al, 2009). The ortholog of CK2 kinase in Drosophila also exerts a crucial circadian function by phosphorylating PER and regulating its nuclear entry (Akten et al, 2003;Lin et al, 2002;Lin et al, 2005).…”

Section: Phosphorylationmentioning

confidence: 99%

“…BMAL1 is also targeted by other kinases, for example by mitogen-activated protein kinases (MAPKs) (Sanada et al, 2002) and CK2 (Tamaru et al, 2009). An important site of CK2 activity is the serine residue at position 90 (S90) in BMAL1, the mutation of which leads to disruptions in circadian rhythmicity (Tamaru et al, 2009).…”

Section: Phosphorylationmentioning

confidence: 99%

Mammalian circadian clock and metabolism – the epigenetic link

Bellet

Sassone–Corsi

2010

Journal of Cell Science

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177

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Circadian rhythms regulate a wide variety of physiological and metabolic processes. The clock machinery comprises complex transcriptional–translational feedback loops that, through the action of specific transcription factors, modulate the expression of as many as 10% of cellular transcripts. This marked change in gene expression necessarily implicates a global regulation of chromatin remodeling. Indeed, various descriptive studies have indicated that histone modifications occur at promoters of clock-controlled genes (CCGs) in a circadian manner. The finding that CLOCK, a transcription factor crucial for circadian function, has intrinsic histone acetyl transferase (HAT) activity has paved the way to unraveling the molecular mechanisms that govern circadian chromatin remodeling. A search for the histone deacetylase (HDAC) that counterbalances CLOCK activity revealed that SIRT1, a nicotinamide adenin dinucleotide (NAD+)-dependent HDAC, functions in a circadian manner. Importantly, SIRT1 is a regulator of aging, inflammation and metabolism. As many transcripts that oscillate in mammalian peripheral tissues encode proteins that have central roles in metabolic processes, these findings establish a functional and molecular link between energy balance, chromatin remodeling and circadian physiology. Here we review recent studies that support the existence of this link and discuss their implications for understanding mammalian physiology and pathology.

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CK2α phosphorylates BMAL1 to regulate the mammalian clock

Cited by 120 publications

References 20 publications

Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA

Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA

CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock

Mammalian circadian clock and metabolism – the epigenetic link

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