DegronMD - O15516(CLOCK)

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, ARNTL/BMAL1, ARNTL2/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 ARNTL/BMAL1 or ARNTL2/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-ARNTL/BMAL1|ARNTL2/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 ARNTL/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-ARNTL/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. The CLOCK-ARNTL2/BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking Ala residue in addition to the canonical 6-nucleotide E-box sequence (PubMed:23229515). CLOCK specifically binds to the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3' (PubMed:23229515). The CLOCK-ARNTL/BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (PubMed:23229515). CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner ARNTL/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 (PubMed:21980503). 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. 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 (By similarity). {ECO:0000250|UniProtKB:O08785, ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:18587630, ECO:0000269|PubMed:21659603, ECO:0000269|PubMed:21980503, ECO:0000269|PubMed:22284746, ECO:0000269|PubMed:23229515, ECO:0000269|PubMed:23785138, ECO:0000269|PubMed:24005054, ECO:0000269|PubMed:28985504}. View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.S431A	TCGA-18-3410	LUSC	TCGA	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation altering degron motif	0.7588
p.S431A	DO26456	LUSC	ICGC	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation altering degron motif	0.7588
p.H442Y	TCGA-VQ-A8PP	STAD	TCGA	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation rewiring degron network	0.0833
p.H442Y	DO51774	STAD	ICGC	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation rewiring degron network	0.0833
p.S427R	DO229038	LICA	ICGC	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation blocking phosphorylation signal	0.75
p.P428R	DO46390	OV	ICGC	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation altering degron motif	0.7512
p.R435L	DO229250	THCA	ICGC	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation rewiring degron network	0.2778
p.R435Q	SIDM00313	Hodgkin's Lymphoma	GDSC	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation rewiring degron network	0.2778
p.R435Q	SIDM01027	Esophageal Squamous Cell Carcinoma	GDSC	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation rewiring degron network	0.2778
p.R435Q	ACH-000702	Lymphoma	CCLE	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation rewiring degron network	0.2778
p.R435Q	ACH-000865	Esophageal Cancer	CCLE	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation rewiring degron network	0.2778
p.R435Q	ACH-001533	Lymphoma	CCLE	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation rewiring degron network	0.2778
p.R435Q	L-1236	haematopoietic and lymphoid tissue	COSMIC	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation rewiring degron network	0.2778
p.R435Q	KYSE-450	oesophagus	COSMIC	PTPSAS	DEG_SCF_FBW7_1	428:433	Mutation rewiring degron network	0.2778

DegronMD: protein-targeted degradation, mutation and drug response to degrons

CLOCK

UniProt ID: O15516

Entrez ID: 9575

Protein name: Circadian locomoter output cycles protein kaput (hCLOCK) (EC 2.3.1.48) (Class E basic helix-loop-helix protein 8) (bHLHe8)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for CLOCK in