Table I. Isolation of mammalian circadian clock genes and mutant phenotypes. Mammalian circadian clock genes have been identified and isolated using various approaches. Their protein products function in the following transcriptional and post-translational mechanisms: CRY1, 2, PER1, 2, DEC1, 2, REV-ERBα, β, γ act as transcriptional repressors. CLOCK, NPA52, BMAL1, and RORα , β, γ are transcriptional activators. CK, δ, ε, and GSK3β are protein kinases. FBXL3 is a substrate recognition protein of an ubiquitin ligase complex. EZH2 is a member of the polycomb protein family, which probably keeps chromatin regions in a transcription-poised state. NONO is an RNA-DNA-binding protein which attenuates the action of PER proteins through yet unidentified mechanisms. CIPC has no recognizable functional peptide motif. period length; nd, not determined; DNA, deoxyribonucleic acid; RNA, ribonucleic acid.

Approach	Gene	Phenotype (wheel running)	References
Genomics	Period 1 (Per1)	KO: τ shorter to arrhythmic	21-23
	Period 2 (Per2)	KO: τ shorter to arrhythmic	21, 23
	Per1/Per2	KO arrhythmic	21, 23
	Cryptochrome 1 (Cry1)	KO: τ shorter	24, 25
	Cryptochrome 2 (Cry2)	KO: τ longer	24, 25
	Cry1/Cry2	KO: arrhythmic	24, 25
	Casein kinase 1δ (Ck1δ	nd	26
	Casein kinase 1ε (Ck1ε)	(see Tau mutation, below)	26
	Npas2	KO: mild circadian phenotypes	27
	Npas2/Clock	KO: arrhythmic	28
Genetics
ENU screen	Clock	Antimorph: τ longer to arrhythmic	29
	Overtime (FbxI3Ovtm)	Hypomorph or null: τ longer	30-32
Spontaneous mutation	Tau (Ck1ε, hamster)	Hypomorph: τ shorter	33
Yeast-two-hybrid assay	Bmal1	KO arrhythmic	34, 35
	Cipc	nd (but depletion in fibroblasts shortens τ)
Biochemistry
Protein-DNA interactions	Rev-erbα	KO: τ shorter	36, 37
	Rev-erbβ
	Rorα	nd (also identified in a screen for as Bmal1 activators)	38, 39
	Rorβ	KO: τ longer	40, 41
	Rorγ	nd (also identified in a screen for as Email activators)	39, 42
Protein-protein	Nono	nd (but required for clock function in fibroblasts)	43
Interactions with Mper1
CLOCK-BMAL1	Ezh2	nd (but required for clock function in fibroblasts)	44
REV-ERB	Gsk3β	nd (but required for normal clock function in fibroblasts)	45