Abstract
Early 2 factor (E2F) family transcription factors participate in myriad cell biological processes including: the cell cycle, DNA repair, apoptosis, development, differentiation, and metabolism. Circadian rhythms influence many of these phenomena. Here we find that a mammalian circadian rhythm component, Cryptochrome 2 (CRY2), regulates E2F family members. Furthermore, CRY1 and CRY2 cooperate with the E3 ligase complex SKP-CULLIN-FBXL3 (SCFFBXL3) to reduce E2F steady state protein levels. These findings reveal an unrecognized molecular connection between circadian clocks and cell cycle regulation and highlight another mechanism to maintain appropriate E2F protein levels for proper cell growth.
Highlights
Circadian rhythms allow organisms to anticipate daily environmental changes in accordance with the Earth’s rotation
As we previously found that Cryptochrome 2 (CRY2) can act as a co-factor for SCFFBXL3 to stimulate ubiquitination and degradation of c-MYC and TLK213,17, we hypothesized that CRY2 could act as a co-factor for Early 2 factor (E2F) family member degradation in a similar manner
We find that E2F target genes are slightly but consistently upregulated in Cry2−/− mouse embryonic fibroblasts (MEFs) compared to matched WT control cells
Summary
Circadian rhythms allow organisms to anticipate daily environmental changes in accordance with the Earth’s rotation. Circadian clocks have been found to influence cell cycle progression, possibly through transcriptional regulation of c-Myc, Ccnd[1], and/or Wee-12,3. PER2 modulates the stability of P5315,16, which could influence the cell cycle in unstressed conditions and help the cell anticipate genotoxic stress Another important protein involved in cell cycle control is c-MYC – a widely known proto-oncogene. The Early 2 Factors (E2Fs) are a family of eight winged-helix transcription factors that are key to regulating cell cycle progression from G1 to S phase among other functions[18,19]. *p < 0.05, **p < 0.01, ****p < 0.0001 by two-way ANOVA with Tukey’s multiple comparisons for effect of genotype These findings highlight a more widespread substrate repertoire of CRY2 and SCFFBXL3 mediated degradation and further supports the interconnection between circadian clocks and cell cycle progression
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