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FUNCTION Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. Regulates the circadian expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an enhancer of the transactivation potential of NF-kappaB. Plays an important role in the homeostatic regulation of sleep. The CLOCK-BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. May play a role in spermatogenesis; contributes to the chromatoid body assembly and physiology. The CLOCK-BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking adenine nucleotide at the 3-prime end of the canonical 6-nucleotide E-box sequence (By similarity). CLOCK specifically binds to the half-site 5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3' (By similarity). The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner BMAL1. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation of multiple lysine residues located in its hinge region. The acetyltransferase activity of CLOCK is as important as its transcription activity in circadian control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian manner (By similarity). Facilitated by BMAL1, rhythmically interacts and acetylates argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian oscillation of arginine biosynthesis and subsequent ureagenesis (PubMed:28985504). Drives the circadian rhythm of blood pressure through transcriptional activation of ATP1B1 (PubMed:30012868).CATALYTIC ACTIVITY L-lysyl-[protein] + acetyl-CoA = N(6)-acetyl-L-lysyl-[protein] + CoA + H(+)SUBUNIT Component of the circadian clock oscillator which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins (PubMed:11779462). Forms a heterodimer with BMAL1 (PubMed:12897057, PubMed:16717091, PubMed:16980631, PubMed:18662546, PubMed:19946213, PubMed:22653727, PubMed:9616112). The CLOCK-BMAL1 heterodimer is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and for phosphorylation of both CLOCK and BMAL1 (PubMed:12897057). Interacts with NR3C1 in a ligand-dependent fashion (PubMed:19141540). Interacts with ESR1 and estrogen stimulates this interaction (By similarity). Interacts with the complex p35/CDK5 (PubMed:24235147). Interacts with RELA/p65 (PubMed:22895791). Interacts with KAT2B, CREBBP and EP300 (By similarity). Interacts with ID1 and ID3 (PubMed:20861012). Interacts with ID2 (PubMed:20861012). Interacts with MTA1 (PubMed:24089055). Interacts with OGA (PubMed:23395175). Interacts with SIRT1 (PubMed:18662546, PubMed:18662547). Interacts with CIPC (PubMed:17310242). Interacts with EZH2 (PubMed:16717091). Interacts with EIF4E, PIWIL1 and DDX4 (PubMed:22900038). Interacts with PER1, PER2, CRY1 and CRY2 and this interaction requires a translocation to the nucleus (PubMed:16717091, PubMed:18430226, PubMed:18662546). Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits transcription activation. Interaction of the CLOCK-BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (By similarity). The CLOCK-BMAL1 heterodimer interacts with GSK3B (PubMed:19946213). Interacts with KDM5A (PubMed:21960634). Interacts with KMT2A; in a circadian manner (PubMed:21113167). Interacts with MYBBP1A (PubMed:19129230). Interacts with THRAP3 (PubMed:24043798). Interacts with MED1; this interaction requires the presence of THRAP3 (PubMed:24043798). Interacts with NCOA2 (PubMed:24529706). The CLOCK-BMAL1 heterodimer interacts with PASD1. Interacts with NDUFA9. Interacts with IMPDH2; in a circadian manner (By similarity). Interacts with ASS1; in a circadian manner (PubMed:28985504). Interacts with PIWIL2 (via PIWI domain) (PubMed:28903391). Interacts with HNF4A (By similarity).INTERACTION Localizes to sites of DNA damage in a H2AX-independent manner (By similarity). Shuttling between the cytoplasm and the nucleus is under circadian regulation and is BMAL1-dependent. Phosphorylated form located in the nucleus predominantly between CT12 and CT21. Nonphosphorylated form found only in the cytoplasm. Sequestered to the cytoplasm in the presence of ID2.ALTERNATIVE PRODUCTS Expressed equally in brain, eye, testes, ovaries, liver, heart, lung, kidney. In the brain, expression is abundant in the suprachiasmatic nuclei (SCN), in the pyriform cortex, and in the hippocampus. Low expression throughout the rest of the brain. Expression does not appear to undergo circadian oscillations.INDUCTION In the SCN, nuclear expression is lowest between CT7 and CT13. Cytoplasmic expression is highest at these times. In liver, peak levels from CT21 to CT3. Expression of both phosphorylated and unphosphorylated forms of BMAL1 with other circadian clock proteins occurs between CT15 and CT18. Expression in the heart oscillates in a circadian manner.DOMAIN Contains a Gln-rich C-terminal domain which could correspond to the transactivation domain.PTM Ubiquitinated, leading to its proteasomal degradation.PTM O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents protein degradation by inhibiting ubiquitination. It also stabilizes the CLOCK-BMAL1 heterodimer thereby increasing CLOCK-BMAL1-mediated transcriptional activation of PER1/2/3 and CRY1/2.PTM Phosphorylation is dependent on the CLOCK-BMAL1 heterodimer formation. Phosphorylation enhances the transcriptional activity, alters the subcellular localization and decreases the stability of the heterodimer by promoting its degradation. Phosphorylation shows circadian variations in the liver: the hyperphosphorylated form peaks at midnight (CT18), while the hypophosphorylated form is abundant throughout the day. May be phosphorylated by CSNK1D and CKSN1E.PTM Sumoylation enhances its transcriptional activity and interaction with ESR1, resulting in up-regulation of ESR1 activity. Estrogen stimulates sumoylation. Desumoylation by SENP1 negatively regulates its transcriptional activity.PTM Undergoes lysosome-mediated degradation in a time-dependent manner in the liver.POLYMORPHISM The naturally-occurring CLOCK variant, missing exon 19 (deletion of AA 514-564) due to an A-->T nucleotide transversion in a splice donor site, forms a heterodimer with DNA, but fails to activate transcription. Homozygous CLOCK mutants have a circadian rhythm that is increased from 3 to 4 hours and usually the circadian rhythmicity is lost at constant darkness. Expression of CLOCK is also reduced. There also exists an alternative spliced CLOCK variant missing both exon 18 and exon 19 (AA 484-564).
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