Pathway Human Homo sapiens

Circadian clock

R-HSA-9909396 in Reactome release 97: a top-level pathway, with 112 genes placed in it by the mapping files and 9 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-9909396 (mouse), R-RNO-9909396 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-9909396.2
Class: TopLevelPathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2025-03-26
Events inside: 9, counted from the record

At the center of the mammalian circadian clock is a negative transcription-translation feedback loop (TTFL) (reviewed in Albrecht 2012, Gustafson and Partch 2015, Cox and Takahashi 2019). In the morning, the BMAL1:CLOCK/NPAS2 heterodimer activates transcription of CRY1, CRY2, PER1, PER2, PER3 and many other circadian-regulated genes. Levels of PER and CRY proteins rise during the day and inhibit their own expression and the expression of other BMAL1:CLOCK/NPAS2-activated genes in the afternoon and evening (inferred from mouse homologs in Cao et al. 2021). During the night, CRY and PER proteins are targeted for degradation by phosphorylation and polyubiquitination, allowing the cycle to commence again in the morning (reviewed in Abdalla et al. 2022).

A secondary loop also exists in the mammalian clock: transcription of the BMAL1, CLOCK, and NPAS2 genes is activated by Retinoid-related orphan receptor-alpha (RORA) and RORC (ROR-gamma) paralogs and repressed by NR1D1 (REV-ERBA), all of which are targets of regulation by BMAL1:CLOCK/NPAS2 and all of which compete for the same ROR regulated elements (RREs, ROREs) in the BMAL1 and CLOCK promoters and in the promoters of many other genes (reviewed in Duez and Staels 2008). This mutual control forms a reinforcing loop of the circadian clock (reviewed in Kim et al. 2022).

BMAL1 can form heterodimers with either CLOCK or NPAS2, which appear to act redundantly but may show different tissue specificity (inferred from mouse homologs in Landgraf et al. 2016, Reick et al. 2001, Peng et al. 2021). After translation in the cytosol, BMAL1 and CLOCK (and probably NPAS2) are phosphorylated, heterodimerize and enter the nucleus (reviewed in Lee et al. 2001, Hirano et al. 2016). The phosphorylated BMAL1:CLOCK heterodimers bind E-box elements (consensus CANNTG) in the promoters of target genes (inferred from mouse homologs in Gekakis et al. 1998) and recruit coactivators to enhance transcription of the target genes. Genes activated by BMAL1:CLOCK are expressed diurnally. DBP is among the genes activated by phosphorylated BMAL1:CLOCK/NPAS2 and binds D-box elements in the promoters of many circadian-regulated genes to increase the amplitude of rhythmic expression (inferred from mouse homologs in Yamaguchi et al. 2000).

The PER genes (PER1, PER2, PER3) and CRY genes (CRY1, CRY2) are also among those activated by BMAL1:CLOCK and BMAL1:NPAS2 (reviewed in Cox and Takahashi 2019). PER gene and CRY gene mRNAs accumulate during the morning and the proteins accumulate during the afternoon. PER and CRY proteins form complexes in the cytosol and these are bound by kinases CSNK1D or CSNK1E, which phosphorylate PER and CRY proteins (reviewed in Narasimamurthy and Virshup 2021). Phosphorylation of the PER:CRY:kinase complex is required for its translocation into the nucleus. CDK5 phosphorylates PER2 at serine residue 396 (serine-394 of the mouse orthologue) in a diurnal fashion. This phosphorylation facilitates interaction with CRY1 and nuclear entry of the PER2-CRY1 complex (Brenna et al. 2019). Within the nucleus the phosphorylated PER:CRY:kinase complexes bind BMAL1:CLOCK heterodimers, inhibiting their transactivation activity and causing dissociation of BMAL1:CLOCK from DNA (inferred from mouse homologs Cao et al. 2021). This reduces transcription of the target genes of BMAL1:CLOCK during the afternoon and evening.

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 112 genes in this human pathway; showing 1 to 100, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 2
Gene	Authority id	Mapping file id	Evidence codes
GeneADRM1	AuthorityHGNC:15759	Mapping file id11047 NCBI file	EvidenceIEA, TAS
GeneATF2	AuthorityHGNC:784	Mapping file id1386 NCBI file	EvidenceIEA
GeneAVP	AuthorityHGNC:894	Mapping file id551 NCBI file	EvidenceIEA
GeneBHLHE40	AuthorityHGNC:1046	Mapping file id8553 NCBI file	EvidenceIEA
GeneBHLHE41	AuthorityHGNC:16617	Mapping file id79365 NCBI file	EvidenceIEA
GeneBMAL1	AuthorityHGNC:701	Mapping file id406 NCBI file	EvidenceIEA, TAS
GeneBMAL2	AuthorityHGNC:18984	Mapping file id56938 NCBI file	EvidenceTAS
GeneBTRC	AuthorityHGNC:1144	Mapping file id8945 NCBI file	EvidenceIEA
GeneCARM1	AuthorityHGNC:23393	Mapping file id10498 NCBI file	EvidenceIEA
GeneCDK5	AuthorityHGNC:1774	Mapping file id1020 NCBI file	EvidenceIEA
GeneCHD9	AuthorityHGNC:25701	Mapping file id80205 NCBI file	EvidenceIEA
GeneCIPC	AuthorityHGNC:20365	Mapping file id85457 NCBI file	EvidenceIEA
GeneCLOCK	AuthorityHGNC:2082	Mapping file id9575 NCBI file	EvidenceIEA, TAS
GeneCPT1A	AuthorityHGNC:2328	Mapping file id1374 NCBI file	EvidenceIEA
GeneCREB1	AuthorityHGNC:2345	Mapping file id1385 NCBI file	EvidenceIEA
GeneCREBBP	AuthorityHGNC:2348	Mapping file id1387 NCBI file	EvidenceIEA
GeneCREM	AuthorityHGNC:2352	Mapping file id1390 NCBI file	EvidenceIEA
GeneCRTC1	AuthorityHGNC:16062	Mapping file id23373 NCBI file	EvidenceIEA
GeneCRTC2	AuthorityHGNC:27301	Mapping file id200186 NCBI file	EvidenceIEA
GeneCRTC3	AuthorityHGNC:26148	Mapping file id64784 NCBI file	EvidenceIEA
GeneCRY1	AuthorityHGNC:2384	Mapping file id1407 NCBI file	EvidenceIEA
GeneCRY2	AuthorityHGNC:2385	Mapping file id1408 NCBI file	EvidenceIEA
GeneCSNK1D	AuthorityHGNC:2452	Mapping file id1453 NCBI file	EvidenceIEA
GeneCSNK1E	AuthorityHGNC:2453	Mapping file id1454 NCBI file	EvidenceIEA
GeneCSNK2A1	AuthorityHGNC:2457	Mapping file id1457 NCBI file	EvidenceIEA
GeneCSNK2A2	AuthorityHGNC:2459	Mapping file id1459 NCBI file	EvidenceIEA
GeneCSNK2B	AuthorityHGNC:2460	Mapping file id1460 NCBI file	EvidenceIEA
GeneCUL1	AuthorityHGNC:2551	Mapping file id8454 NCBI file	EvidenceIEA
GeneDBP	AuthorityHGNC:2697	Mapping file id1628 NCBI file	EvidenceIEA
GeneELOVL3	AuthorityHGNC:18047	Mapping file idENSG00000119915 Ensembl file	EvidenceIEA
GeneEP300	AuthorityHGNC:3373	Mapping file id2033 NCBI file	EvidenceIEA
GeneF7	AuthorityHGNC:3544	Mapping file id2155 NCBI file	EvidenceIEA
GeneFBXL3	AuthorityHGNC:13599	Mapping file id26224 NCBI file	EvidenceIEA
GeneFBXW11	AuthorityHGNC:13607	Mapping file id23291 NCBI file	EvidenceIEA
GeneHDAC3	AuthorityHGNC:4854	Mapping file id8841 NCBI file	EvidenceIEA, TAS
GeneHELZ2	AuthorityHGNC:30021	Mapping file id85441 NCBI file	EvidenceIEA
GeneKLF15	AuthorityHGNC:14536	Mapping file id28999 NCBI file	EvidenceIEA
GeneKMT2A	AuthorityHGNC:7132	Mapping file id4297 NCBI file	EvidenceIEA
GeneMED1	AuthorityHGNC:9234	Mapping file id5469 NCBI file	EvidenceIEA
GeneMEF2C	AuthorityHGNC:6996	Mapping file id4208 NCBI file	EvidenceIEA
GeneMEF2D	AuthorityHGNC:6997	Mapping file id4209 NCBI file	EvidenceIEA
GeneNAMPT	AuthorityHGNC:30092	Mapping file id10135 NCBI file	EvidenceIEA
GeneNCOA1	AuthorityHGNC:7668	Mapping file id8648 NCBI file	EvidenceIEA
GeneNCOA2	AuthorityHGNC:7669	Mapping file id10499 NCBI file	EvidenceIEA
GeneNCOA6	AuthorityHGNC:15936	Mapping file id23054 NCBI file	EvidenceIEA
GeneNCOR1	AuthorityHGNC:7672	Mapping file id9611 NCBI file	EvidenceIEA, TAS
GeneNOCT	AuthorityHGNC:14254	Mapping file id25819 NCBI file	EvidenceTAS
GeneNPAS2	AuthorityHGNC:7895	Mapping file id4862 NCBI file	EvidenceIEA
GeneNR1D1	AuthorityHGNC:7962	Mapping file id9572 NCBI file	EvidenceIEA, TAS
GeneNRIP1	AuthorityHGNC:8001	Mapping file id8204 NCBI file	EvidenceIEA
GenePER1	AuthorityHGNC:8845	Mapping file id5187 NCBI file	EvidenceIEA, TAS
GenePER2	AuthorityHGNC:8846	Mapping file id8864 NCBI file	EvidenceIEA, TAS
GenePER3	AuthorityHGNC:8847	Mapping file id8863 NCBI file	EvidenceIEA, TAS
GenePPARA	AuthorityHGNC:9232	Mapping file id5465 NCBI file	EvidenceIEA
GenePPARGC1A	AuthorityHGNC:9237	Mapping file id10891 NCBI file	EvidenceIEA
GenePPP1CA	AuthorityHGNC:9281	Mapping file id5499 NCBI file	EvidenceIEA
GenePPP1CB	AuthorityHGNC:9282	Mapping file id5500 NCBI file	EvidenceIEA
GenePPP1CC	AuthorityHGNC:9283	Mapping file id5501 NCBI file	EvidenceIEA
GenePSMA1	AuthorityHGNC:9530	Mapping file id5682 NCBI file	EvidenceIEA, TAS
GenePSMA2	AuthorityHGNC:9531	Mapping file id5683 NCBI file	EvidenceIEA, TAS
GenePSMA3	AuthorityHGNC:9532	Mapping file id5684 NCBI file	EvidenceIEA, TAS
GenePSMA4	AuthorityHGNC:9533	Mapping file id5685 NCBI file	EvidenceIEA, TAS
GenePSMA5	AuthorityHGNC:9534	Mapping file id5686 NCBI file	EvidenceIEA, TAS
GenePSMA6	AuthorityHGNC:9535	Mapping file id5687 NCBI file	EvidenceIEA, TAS
GenePSMA7	AuthorityHGNC:9536	Mapping file id5688 NCBI file	EvidenceIEA, TAS
GenePSMB1	AuthorityHGNC:9537	Mapping file id5689 NCBI file	EvidenceIEA, TAS
GenePSMB2	AuthorityHGNC:9539	Mapping file id5690 NCBI file	EvidenceIEA, TAS
GenePSMB3	AuthorityHGNC:9540	Mapping file id5691 NCBI file	EvidenceIEA, TAS
GenePSMB4	AuthorityHGNC:9541	Mapping file id5692 NCBI file	EvidenceIEA, TAS
GenePSMB5	AuthorityHGNC:9542	Mapping file id5693 NCBI file	EvidenceIEA, TAS
GenePSMB6	AuthorityHGNC:9543	Mapping file id5694 NCBI file	EvidenceIEA, TAS
GenePSMB7	AuthorityHGNC:9544	Mapping file id5695 NCBI file	EvidenceIEA, TAS
GenePSMC1	AuthorityHGNC:9547	Mapping file id5700 NCBI file	EvidenceIEA, TAS
GenePSMC2	AuthorityHGNC:9548	Mapping file id5701 NCBI file	EvidenceIEA, TAS
GenePSMC3	AuthorityHGNC:9549	Mapping file id5702 NCBI file	EvidenceIEA, TAS
GenePSMC4	AuthorityHGNC:9551	Mapping file id5704 NCBI file	EvidenceIEA, TAS
GenePSMC5	AuthorityHGNC:9552	Mapping file id5705 NCBI file	EvidenceIEA, TAS
GenePSMC6	AuthorityHGNC:9553	Mapping file id5706 NCBI file	EvidenceIEA, TAS
GenePSMD1	AuthorityHGNC:9554	Mapping file id5707 NCBI file	EvidenceIEA, TAS
GenePSMD11	AuthorityHGNC:9556	Mapping file id5717 NCBI file	EvidenceIEA, TAS
GenePSMD12	AuthorityHGNC:9557	Mapping file id5718 NCBI file	EvidenceIEA, TAS
GenePSMD13	AuthorityHGNC:9558	Mapping file id5719 NCBI file	EvidenceIEA, TAS
GenePSMD14	AuthorityHGNC:16889	Mapping file id10213 NCBI file	EvidenceIEA, TAS
GenePSMD2	AuthorityHGNC:9559	Mapping file id5708 NCBI file	EvidenceIEA, TAS
GenePSMD3	AuthorityHGNC:9560	Mapping file id5709 NCBI file	EvidenceIEA, TAS
GenePSMD6	AuthorityHGNC:9564	Mapping file id9861 NCBI file	EvidenceIEA, TAS
GenePSMD7	AuthorityHGNC:9565	Mapping file id5713 NCBI file	EvidenceIEA, TAS
GenePSMD8	AuthorityHGNC:9566	Mapping file id5714 NCBI file	EvidenceIEA, TAS
GeneRAI1	AuthorityHGNC:9834	Mapping file id10743 NCBI file	EvidenceIEA
GeneRBM4	AuthorityHGNC:9901	Mapping file id5936 NCBI file	EvidenceIEA
GeneRBX1	AuthorityHGNC:9928	Mapping file id9978 NCBI file	EvidenceIEA
GeneRORA	AuthorityHGNC:10258	Mapping file id6095 NCBI file	EvidenceIEA
GeneRORB	AuthorityHGNC:10259	Mapping file id6096 NCBI file	EvidenceIEA
GeneRORC	AuthorityHGNC:10260	Mapping file id6097 NCBI file	EvidenceIEA
GeneRPS27A	AuthorityHGNC:10417	Mapping file id6233 NCBI file	EvidenceIEA, TAS
GeneRXRA	AuthorityHGNC:10477	Mapping file id6256 NCBI file	EvidenceIEA
GeneSEM1	AuthorityHGNC:10845	Mapping file id7979 NCBI file	EvidenceIEA, TAS
GeneSERPINE1	AuthorityHGNC:8583	Mapping file id5054 NCBI file	EvidenceTAS
GeneSIK1	AuthorityHGNC:11142	Mapping file id150094 NCBI file	EvidenceIEA
GeneSIRT1	AuthorityHGNC:14929	Mapping file id23411 NCBI file	EvidenceIEA

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

None: this is a top-level pathway of the release.

Children

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.