CLOCK clock circadian regulator [Homo sapiens (human)] - Gene

Summary

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Official Symbol: CLOCKprovided by HGNC
Official Full Name: clock circadian regulatorprovided by HGNC
Primary source: HGNC:HGNC:2082
See related: Ensembl:ENSG00000134852 MIM:601851
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: KAT13D; bHLHe8
Summary: The protein encoded by this gene plays a central role in the regulation of circadian rhythms. The protein encodes a transcription factor of the basic helix-loop-helix (bHLH) family and contains DNA binding histone acetyltransferase activity. The encoded protein forms a heterodimer with ARNTL (BMAL1) that binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/ARNTL complexes. Polymorphisms in this gene may be associated with behavioral changes in certain populations and with obesity and metabolic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
Expression: Ubiquitous expression in testis (RPKM 7.8), thyroid (RPKM 6.2) and 24 other tissues See more
Orthologs: mouse all

Annotation release	Status	Assembly	Chr	Location
109.20200228	current	GRCh38.p13 (GCF_000001405.39)	4	NC_000004.12 (55427901..55547138, complement)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	4	NC_000004.11 (56294068..56413076, complement)

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

The study indicates that SNPs in CLOCK genes might contribute to the clinical outcome of gastric cancer through their impact on gene expression.
Title: Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer.
heme disrupts binding of CLOCK to its E-box DNA target
Title: Heme binding to human CLOCK affects interactions with the E-box.
Study showed that abnormal expression levels of Per2, Clock, and Bmal1 were detected in patients with traumatic brain injury-related sleep disorders.
Title: Regulation of Circadian Clock Genes on Sleep Disorders in Traumatic Brain Injury Patients.
The aim of this study was to investigate, in fibroblasts from genetic Parkinson's disease patients carrying parkin mutations, the interplay between mitochondrial bioenergetics and the cell autonomous circadian clock.
Title: Parkin Mutation Affects Clock Gene-Dependent Energy Metabolism.
identified a new protein-protein interaction mechanism in which CLOCK can directly regulate cell metabolism via the mitochondrial membrane transporter SLC25A10.
Title: The circadian protein CLOCK regulates cell metabolism via the mitochondrial carrier SLC25A10.
Eight CLOCK SNPs are associated with ADHD risk in Brazilian population.
Title: <i>CLOCK</i> Polymorphisms in Attention-Deficit/Hyperactivity Disorder (ADHD): Further Evidence Linking Sleep and Circadian Disturbances and ADHD.
Loss of protective endothelial CLOCK expression aggravates TGF-beta/ROCK1-modulated endothelial to mesenchymal transition progression, which contributes to the vulnerability of human carotid plaque.
Title: Loss of CLOCK under high glucose upregulates ROCK1-mediated endothelial to mesenchymal transition and aggravates plaque vulnerability.
the messenger RNA expression of brain and muscle ARNT-like 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) genes is altered by low doses (5 mJ/cm(2) ) of ultraviolet B in the immortalized HaCat human keratinocyte cell line.
Title: BMAL1 and CLOCK proteins in regulating UVB-induced apoptosis and DNA damage responses in human keratinocytes.
The frequency of the TT-genotype and 3111T-allele of the Clock 3111T/C gene polymorphic marker in the Caucasian women with insomnia is higher as compared to control.
Title: Association of the melatonin circadian rhythms with clock 3111T/C gene polymorphism in Caucasian and Asian menopausal women with insomnia.
We found a significant association with CLOCK rs12649507 and cluster headache
Title: A genetic CLOCK variant associated with cluster headache causing increased mRNA levels.

Submit: New GeneRIF Correction See all GeneRIFs (187)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

NHGRI GWAS Catalog

Description
Genome-wide association scan for five major dimensions of personality. NHGRI GWA Catalog NHGRI GWA CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Replication interactions

Interaction	Pubs
Knockdown of clock homolog (mouse, CLOCK) by siRNA inhibits the early stages of HIV-1 replication in 293T cells infected with VSV-G pseudotyped HIV-1	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

STS-R80639 (e-PCR)
- UniSTS:75273

SHGC-50712 (e-PCR)
- UniSTS:37

G54151 (e-PCR)
- UniSTS:109388

SHGC-59220 (e-PCR)
- UniSTS:25995

SHGC-67841 (e-PCR)
- UniSTS:49806

SHGC-106039 (e-PCR)
- UniSTS:169617

G16718 (e-PCR)
- UniSTS:75424

PMC55343P8 (e-PCR)
- UniSTS:273331

RH121148 (e-PCR)
- UniSTS:134143

Homology

Homologs of the CLOCK gene: The CLOCK gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.
Orthologs from Annotation Pipeline: 312 organisms have orthologs with human gene CLOCK
Orthologs

Clone Names

FLJ39000, FLJ42446, KIAA0334, DKFZp686I23208

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
DNA binding	IDA Inferred from Direct Assay more info	PubMed
DNA-binding transcription activator activity, RNA polymerase II-specific	ISS Inferred from Sequence or Structural Similarity more info
DNA-binding transcription factor activity	ISS Inferred from Sequence or Structural Similarity more info
DNA-binding transcription factor activity, RNA polymerase II-specific	ISA Inferred from Sequence Alignment more info
DNA-binding transcription factor activity, RNA polymerase II-specific	ISM Inferred from Sequence Model more info	PubMed
DNA-binding transcription factor activity, RNA polymerase II-specific	ISS Inferred from Sequence or Structural Similarity more info
E-box binding	IDA Inferred from Direct Assay more info	PubMed
RNA polymerase II proximal promoter sequence-specific DNA binding	IDA Inferred from Direct Assay more info	PubMed
RNA polymerase II proximal promoter sequence-specific DNA binding	ISS Inferred from Sequence or Structural Similarity more info
chromatin DNA binding	ISS Inferred from Sequence or Structural Similarity more info
histone acetyltransferase activity	IMP Inferred from Mutant Phenotype more info	PubMed
protein binding	IPI Inferred from Physical Interaction more info	PubMed
protein dimerization activity	IEA Inferred from Electronic Annotation more info
sequence-specific DNA binding	ISS Inferred from Sequence or Structural Similarity more info

Process	Evidence Code	Pubs
DNA damage checkpoint	IMP Inferred from Mutant Phenotype more info	PubMed
cellular response to ionizing radiation	IDA Inferred from Direct Assay more info	PubMed
circadian regulation of gene expression	IDA Inferred from Direct Assay more info	PubMed
circadian regulation of gene expression	IMP Inferred from Mutant Phenotype more info	PubMed
circadian regulation of gene expression	ISS Inferred from Sequence or Structural Similarity more info
circadian rhythm	TAS Traceable Author Statement more info
histone acetylation	IEA Inferred from Electronic Annotation more info
negative regulation of glucocorticoid receptor signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of transcription, DNA-templated	ISS Inferred from Sequence or Structural Similarity more info
photoperiodism	TAS Traceable Author Statement more info	PubMed
positive regulation of NF-kappaB transcription factor activity	ISS Inferred from Sequence or Structural Similarity more info
positive regulation of inflammatory response	IEA Inferred from Electronic Annotation more info
positive regulation of transcription by RNA polymerase II	IGI Inferred from Genetic Interaction more info	PubMed
positive regulation of transcription, DNA-templated	IDA Inferred from Direct Assay more info	PubMed
positive regulation of transcription, DNA-templated	ISS Inferred from Sequence or Structural Similarity more info
proteasome-mediated ubiquitin-dependent protein catabolic process	ISS Inferred from Sequence or Structural Similarity more info
protein acetylation	IDA Inferred from Direct Assay more info	PubMed
regulation of circadian rhythm	ISS Inferred from Sequence or Structural Similarity more info
regulation of hair cycle	IMP Inferred from Mutant Phenotype more info	PubMed
regulation of insulin secretion	ISS Inferred from Sequence or Structural Similarity more info
regulation of transcription by RNA polymerase II	TAS Traceable Author Statement more info	PubMed
regulation of transcription, DNA-templated	ISS Inferred from Sequence or Structural Similarity more info
regulation of type B pancreatic cell development	ISS Inferred from Sequence or Structural Similarity more info
response to redox state	IDA Inferred from Direct Assay more info	PubMed
signal transduction	TAS Traceable Author Statement more info	PubMed
spermatogenesis	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
chromatoid body	ISS Inferred from Sequence or Structural Similarity more info
chromosome	IDA Inferred from Direct Assay more info	PubMed
cytosol	IDA Inferred from Direct Assay more info	PubMed
intracellular membrane-bounded organelle	IDA Inferred from Direct Assay more info
nuclear chromatin	ISA Inferred from Sequence Alignment more info
nucleoplasm	IDA Inferred from Direct Assay more info
nucleoplasm	TAS Traceable Author Statement more info
nucleus	IDA Inferred from Direct Assay more info	PubMed
transcription factor complex	IPI Inferred from Physical Interaction more info	PubMed

General protein information

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Preferred Names: circadian locomoter output cycles protein kaput

Names: circadian locomoter output cycles kaput protein; class E basic helix-loop-helix protein 8; clock homolog

NP_001254772.1

EC 2.3.1.48

NP_004889.1

EC 2.3.1.48

XP_005265844.1

EC 2.3.1.48

XP_011532711.1

EC 2.3.1.48

XP_011532712.1

EC 2.3.1.48

XP_011532713.1

EC 2.3.1.48

XP_016864343.1

EC 2.3.1.48

XP_016864344.1

EC 2.3.1.48

XP_024310052.1

EC 2.3.1.48

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

mRNA and Protein(s)

NM_001267843.1 → NP_001254772.1 circadian locomoter output cycles protein kaput

See identical proteins and their annotated locations for NP_001254772.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longer transcript. Both variants 1 and 2 encode the same protein.

Source sequence(s)

AC069200, BC041878

Consensus CDS

CCDS3500.1

UniProtKB/Swiss-Prot

O15516

UniProtKB/TrEMBL

Q3ZCT4

Related

ENSP00000370723.1, ENST00000381322.5

Conserved Domains (4) summary

cd00083
Location:32 → 86

HLH; Helix-loop-helix domain, found in specific DNA- binding proteins that act as transcription factors; 60-100 amino acids long. A DNA-binding basic region is followed by two alpha-helices separated by a variable loop region; HLH forms homo- and heterodimers, ...

pfam00989
Location:109 → 175

PAS; PAS fold

pfam09606
Location:496 → 686

Med15; ARC105 or Med15 subunit of Mediator complex non-fungal

cl25986
Location:274 → 377

PAS_3; PAS fold
NM_004898.4 → NP_004889.1 circadian locomoter output cycles protein kaput

See identical proteins and their annotated locations for NP_004889.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) differs in the 5' UTR compared to variant 1. Both variants 1 and 2 encode the same protein.

Source sequence(s)

AC069200, AK223549, DA658950

Consensus CDS

CCDS3500.1

UniProtKB/Swiss-Prot

O15516

UniProtKB/TrEMBL

Q53EU0

Related

ENSP00000426983.1, ENST00000513440.6

Conserved Domains (4) summary

cd00083
Location:32 → 86

HLH; Helix-loop-helix domain, found in specific DNA- binding proteins that act as transcription factors; 60-100 amino acids long. A DNA-binding basic region is followed by two alpha-helices separated by a variable loop region; HLH forms homo- and heterodimers, ...

pfam00989
Location:109 → 175

PAS; PAS fold

pfam09606
Location:496 → 686

Med15; ARC105 or Med15 subunit of Mediator complex non-fungal

cl25986
Location:274 → 377

PAS_3; PAS fold

RefSeqs of Annotated Genomes: Homo sapiens Updated Annotation Release 109.

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p13 Primary Assembly

Genomic

NC_000004.12 Reference GRCh38.p13 Primary Assembly

Range

55427901..55547138 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_017008854.1 → XP_016864343.1 circadian locomoter output cycles protein kaput isoform X1

UniProtKB/Swiss-Prot

O15516

Conserved Domains (4) summary

cd00083
Location:32 → 86

HLH; Helix-loop-helix domain, found in specific DNA- binding proteins that act as transcription factors; 60-100 amino acids long. A DNA-binding basic region is followed by two alpha-helices separated by a variable loop region; HLH forms homo- and heterodimers, ...

pfam00989
Location:109 → 175

PAS; PAS fold

pfam09606
Location:496 → 686

Med15; ARC105 or Med15 subunit of Mediator complex non-fungal

cl25986
Location:274 → 377

PAS_3; PAS fold
XM_011534410.2 → XP_011532712.1 circadian locomoter output cycles protein kaput isoform X1

See identical proteins and their annotated locations for XP_011532712.1

UniProtKB/Swiss-Prot

O15516

Conserved Domains (4) summary

cd00083
Location:32 → 86

HLH; Helix-loop-helix domain, found in specific DNA- binding proteins that act as transcription factors; 60-100 amino acids long. A DNA-binding basic region is followed by two alpha-helices separated by a variable loop region; HLH forms homo- and heterodimers, ...

pfam00989
Location:109 → 175

PAS; PAS fold

pfam09606
Location:496 → 686

Med15; ARC105 or Med15 subunit of Mediator complex non-fungal

cl25986
Location:274 → 377

PAS_3; PAS fold
XM_005265787.2 → XP_005265844.1 circadian locomoter output cycles protein kaput isoform X1

See identical proteins and their annotated locations for XP_005265844.1

UniProtKB/Swiss-Prot

O15516

Conserved Domains (4) summary

cd00083
Location:32 → 86

HLH; Helix-loop-helix domain, found in specific DNA- binding proteins that act as transcription factors; 60-100 amino acids long. A DNA-binding basic region is followed by two alpha-helices separated by a variable loop region; HLH forms homo- and heterodimers, ...

pfam00989
Location:109 → 175

PAS; PAS fold

pfam09606
Location:496 → 686

Med15; ARC105 or Med15 subunit of Mediator complex non-fungal

cl25986
Location:274 → 377

PAS_3; PAS fold
XM_011534411.2 → XP_011532713.1 circadian locomoter output cycles protein kaput isoform X1

See identical proteins and their annotated locations for XP_011532713.1

UniProtKB/Swiss-Prot

O15516

Conserved Domains (4) summary

cd00083
Location:32 → 86

HLH; Helix-loop-helix domain, found in specific DNA- binding proteins that act as transcription factors; 60-100 amino acids long. A DNA-binding basic region is followed by two alpha-helices separated by a variable loop region; HLH forms homo- and heterodimers, ...

pfam00989
Location:109 → 175

PAS; PAS fold

pfam09606
Location:496 → 686

Med15; ARC105 or Med15 subunit of Mediator complex non-fungal

cl25986
Location:274 → 377

PAS_3; PAS fold
XM_024454284.1 → XP_024310052.1 circadian locomoter output cycles protein kaput isoform X1

Conserved Domains (4) summary

cd00083
Location:32 → 86

HLH; Helix-loop-helix domain, found in specific DNA- binding proteins that act as transcription factors; 60-100 amino acids long. A DNA-binding basic region is followed by two alpha-helices separated by a variable loop region; HLH forms homo- and heterodimers, ...

pfam00989
Location:109 → 175

PAS; PAS fold

pfam09606
Location:496 → 686

Med15; ARC105 or Med15 subunit of Mediator complex non-fungal

cl25986
Location:274 → 377

PAS_3; PAS fold
XM_011534409.2 → XP_011532711.1 circadian locomoter output cycles protein kaput isoform X1

See identical proteins and their annotated locations for XP_011532711.1

UniProtKB/Swiss-Prot

O15516

Conserved Domains (4) summary

cd00083
Location:32 → 86

HLH; Helix-loop-helix domain, found in specific DNA- binding proteins that act as transcription factors; 60-100 amino acids long. A DNA-binding basic region is followed by two alpha-helices separated by a variable loop region; HLH forms homo- and heterodimers, ...

pfam00989
Location:109 → 175

PAS; PAS fold

pfam09606
Location:496 → 686

Med15; ARC105 or Med15 subunit of Mediator complex non-fungal

cl25986
Location:274 → 377

PAS_3; PAS fold
XM_017008855.1 → XP_016864344.1 circadian locomoter output cycles protein kaput isoform X2