CRY1CRY2

CRY1 and CRY2, collectively referred to as CRY1CRY2 in this context, are mammalian cryptochrome proteins that belong to the cryptochrome/photolyase family. They are encoded by the CRY1 and CRY2 genes and are considered core components of the cellular circadian clock in mammals. They are homologous to Drosophila cryptochrome but serve primarily as transcriptional repressors in mammals rather than as primary light sensors.

In the mammalian circadian clock, CRY1 and CRY2 form part of a negative feedback loop with the transcription factors CLOCK and BMAL1. Together they repress CLOCK-BMAL1-driven transcription of clock genes, including their own, helping to generate and stabilize ~24-hour rhythms in physiological processes. CRYs accumulate in the nucleus and interact with other clock proteins such as PERs and histone-modifying factors to regulate gene expression. Light information reaches the central clock primarily through retinal mechanisms; in mammals, CRYs are not the primary photoreceptors, and their activity is modulated by light indirectly via signaling pathways that affect protein stability and interactions.

Structurally, CRY1 and CRY2 possess a conserved N-terminal photolyase-like domain and a C-terminal regulatory tail. Although they share substantial sequence similarity, CRY1 and CRY2 differ in tissue distribution, stability, and specific regulatory interactions, contributing to distinct effects on circadian period and amplitude. They are broadly expressed, with rhythmic patterns in the suprachiasmatic nucleus and peripheral tissues, reflecting their central role in coordinating daily physiology.

Beyond timekeeping, CRY1 and CRY2 influence metabolism, drug response, mood-related traits, and cancer risk in humans, with genetic variation in these genes associated with chronotype and metabolic traits in some studies. Double knockout of CRY genes in animals abolishes rhythmicity, underscoring their essential role in the circadian system.