======= CLOCK =======
== Gene Information ==
* **Official Symbol**: CLOCK
* **Official Name**: clock circadian regulator
* **Aliases and Previous Symbols**: N/A
* **Entrez ID**: [[https://www.ncbi.nlm.nih.gov/gene/?term=9575|9575]]
* **UniProt**: [[https://www.uniprot.org/uniprot/O15516|O15516]]
* **Interactions**: [[https://thebiogrid.org/search.php?search=CLOCK&organism=9606|BioGRID]]
* **PubMed articles**: [[https://www.ncbi.nlm.nih.gov/pubmed/?term=gene%20CLOCK|Open PubMed]]
* **OMIM**: [[https://omim.org/entry/601851|Open OMIM]]
== Function Summary ==
* **Entrez Summary**: N/A
* **UniProt Summary**: 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). {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}.
|PAS 3|
|HLH|
|PAS|
|negative regulation of glucocorticoid receptor signaling pathway|
|regulation of glucocorticoid receptor signaling pathway|
|regulation of type B pancreatic cell development|
|chromatoid body|
|response to redox state|
|photoperiodism|
|regulation of hair cycle|
|negative regulation of intracellular steroid hormone receptor signaling pathway|
|histone acetyltransferase activity|
|E-box binding|
|circadian regulation of gene expression|
|cellular response to ionizing radiation|
|chromatin DNA binding|
|regulation of intracellular steroid hormone receptor signaling pathway|
|RNA polymerase II distal enhancer sequence-specific DNA binding|
|histone acetylation|
|regulation of circadian rhythm|
|internal peptidyl-lysine acetylation|
|peptidyl-lysine acetylation|
|internal protein amino acid acetylation|
|chromosome|
|DNA damage checkpoint|
|positive regulation of inflammatory response|
|circadian rhythm|
|regulation of epithelial cell differentiation|
|protein acetylation|
|DNA integrity checkpoint|
|response to ionizing radiation|
|positive regulation of NF-kappaB transcription factor activity|
|protein dimerization activity|
|cellular response to radiation|
|regulation of insulin secretion|
|protein acylation|
|cell cycle checkpoint|
|transcription factor complex|
|regulation of peptide hormone secretion|
|positive regulation of DNA-binding transcription factor activity|
|regulation of hormone secretion|
|rhythmic process|
|response to light stimulus|
|peptidyl-lysine modification|
|cellular response to environmental stimulus|
|cellular response to abiotic stimulus|
|proteasome-mediated ubiquitin-dependent protein catabolic process|
|regulation of inflammatory response|
|proteasomal protein catabolic process|
|histone modification|
|covalent chromatin modification|
|sequence-specific DNA binding|
|regulation of DNA-binding transcription factor activity|
|response to radiation|
|DNA-binding transcription activator activity, RNA polymerase II-specific|
|regulation of protein secretion|
|positive regulation of defense response|
|regulation of peptide secretion|
|RNA polymerase II proximal promoter sequence-specific DNA binding|
|ubiquitin-dependent protein catabolic process|
|modification-dependent protein catabolic process|
|regulation of hormone levels|
|spermatogenesis|
|modification-dependent macromolecule catabolic process|
|male gamete generation|
|negative regulation of cell cycle|
|proteolysis involved in cellular protein catabolic process|
|positive regulation of response to external stimulus|
|cellular protein catabolic process|
|DNA-binding transcription factor activity|
|protein catabolic process|
|intracellular membrane-bounded organelle|
|gamete generation|
|chromatin organization|
|regulation of protein transport|
|regulation of peptide transport|
|regulation of establishment of protein localization|
|regulation of secretion by cell|
|regulation of defense response|
|cellular response to DNA damage stimulus|
|regulation of secretion|
|multicellular organismal reproductive process|
|sexual reproduction|
|multicellular organism reproduction|
|peptidyl-amino acid modification|
|cellular macromolecule catabolic process|
|regulation of cell development|
|multi-organism reproductive process|
|regulation of protein localization|
|macromolecule catabolic process|
|organonitrogen compound catabolic process|
|chromosome organization|
|regulation of response to external stimulus|
|response to abiotic stimulus|
|regulation of cell cycle|
|negative regulation of transcription, DNA-templated|
|positive regulation of transcription by RNA polymerase II|
|negative regulation of nucleic acid-templated transcription|
|negative regulation of RNA biosynthetic process|
|negative regulation of signal transduction|
|proteolysis|
|negative regulation of RNA metabolic process|
|negative regulation of cell communication|
|negative regulation of signaling|
|negative regulation of cellular macromolecule biosynthetic process|
|reproductive process|
|reproduction|
|negative regulation of nucleobase-containing compound metabolic process|
|DNA binding|
|negative regulation of macromolecule biosynthetic process|
|regulation of response to stress|
|negative regulation of cellular biosynthetic process|
|positive regulation of transcription, DNA-templated|
|negative regulation of biosynthetic process|
|DNA-binding transcription factor activity, RNA polymerase II-specific|
|negative regulation of response to stimulus|
|positive regulation of nucleic acid-templated transcription|
|positive regulation of RNA biosynthetic process|
|cellular response to stress|
|negative regulation of gene expression|
|positive regulation of RNA metabolic process|
|organic substance catabolic process|
|positive regulation of molecular function|
|cellular catabolic process|
|regulation of cell differentiation|
|regulation of transport|
|positive regulation of nucleobase-containing compound metabolic process|
|positive regulation of macromolecule biosynthetic process|
|positive regulation of cellular biosynthetic process|
|positive regulation of gene expression|
|positive regulation of biosynthetic process|
\\
=== CRISPR Data ===
^Screen^Score^
|[[:results:exp113|1-Methyl-nicotinamide-chloride 1000μM R03 exp113]]|1.88|
|[[:results:exp280|Daidzin 10μM R06 exp280]]|1.95|
No correlation found to any other genes in chemogenomics.
Global Fraction of Cell Lines Where Essential: 0/739
^Tissue^Fraction Of Cell Lines Where Essential^
|1290807.0|0/1|
|909776.0|0/1|
|bile duct|0/28|
|blood|0/28|
|bone|0/26|
|breast|0/33|
|central nervous system|0/56|
|cervix|0/4|
|colorectal|0/17|
|esophagus|0/13|
|fibroblast|0/1|
|gastric|0/16|
|kidney|0/21|
|liver|0/20|
|lung|0/75|
|lymphocyte|0/16|
|ovary|0/26|
|pancreas|0/24|
|peripheral nervous system|0/16|
|plasma cell|0/15|
|prostate|0/1|
|skin|0/24|
|soft tissue|0/9|
|thyroid|0/2|
|upper aerodigestive|0/22|
|urinary tract|0/29|
|uterus|0/5|
== Essentiality in NALM6 ==
* **Essentiality Rank**: 17008
* **Expression level (log2 read counts)**: 5.39
{{:chemogenomics:nalm6 dist.png?nolink |}}