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Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-9931510

PubChem

R-HSA-9931510

Description

After translocation into the nucleus, the phosphorylated BMAL1:CLOCK heterodimer and, by inference, the BMAL1:NPAS2 heterodimer activate transcription by binding E-box elements (consensus: CANNTG) in the promoters of more than 2000 target genes (inferred from mouse homologs in Hatanaka et al. 2010, Guillaume et al. 2011) and recruiting coactivators such as CREB-binding protein (CREBBP) (inferred from mouse homologs in Garg et al. 2019), the histone methylase KMT2A (MLL1) and, presumably, components of the MLL1 complex (inferred from mouse homologs in Katada and Sassone-Corsi 2010). Transcriptional activation by BMAL1:CLOCK occurs during the day, thus genes regulated by BMAL1:CLOCK are diurnally expressed.
Among the thousands of genes activated by BMAL1:CLOCK are the Cryptochrome genes (CRY1, CRY2) and the Period genes (PER1, PER2, PER3) that encode proteins that repress BMAL1:CLOCK activity, forming the primary loop of the circadian clock (reviewed in Cox and Takahashi 2019). BMAL1:CLOCK also activates the expression of Retinoid-related orphan receptor genes RORA, RORB, and RORC and the heme-binding nuclear receptor gene NR1D1 (REV-ERBA) that bind the same ROR responsive elements (RRE, RORE) in the promoters of the BMAL1, CLOCK, and NPAS2 genes. RORA, RORB, RORC activate expression; NR1D1 represses expression. The reciprocal regulation of BMAL1:CLOCK and RORA, RORB, RORC, NR1D1 forms the secondary loop of the circadian clock.

Click on a node on the pathway to see its details. Glycoproteins are marked with a glycoprotein icon in their name.

SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

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UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
O00327	Basic helix-loop-helix ARNT-like protein 1	ARNTL BHLHE5 BMAL1 MOP3 PASD3	view
O15055	Period circadian protein homolog 2	KIAA0347 PER2	view
O15516	Circadian locomoter output cycles protein kaput	BHLHE8 CLOCK KIAA0334	view
O15534	Period circadian protein homolog 1	KIAA0482 PER PER1 RIGUI	view
P19484	Transcription factor EB	BHLHE35 TFEB	view
P35398	Nuclear receptor ROR-alpha	NR1F1 RORA RZRA	view
P56645	Period circadian protein homolog 3	GIG13 PER3	view
P57059	Serine/threonine-protein kinase SIK1	SIK SIK1 SNF1LK	view
Q03164	Histone-lysine N-methyltransferase 2A	ALL1 CXXC7 HRX HTRX KMT2A MLL MLL1 TRX1	view
Q6UUV9	CREB-regulated transcription coactivator 1	CRTC1 KIAA0616 MECT1 TORC1 WAMTP1	view

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