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Cal-Kayitmazbatir S , Kulkoyluoglu-Cotul E , Growe J , Selby CP , Rhoades SD , Malik D , Oner H , Asimgil H , Francey LJ , Sancar A , Kruger WD , Hogenesch JB , Weljie A , Anafi RC , Kavakli IH
CRY1-CBS binding regulates circadian clock function and metabolism
FEBS J. 2021 Jan;288(2) :614-639
PMID: 32383312    PMCID: PMC7648728    URL: https://www.ncbi.nlm.nih.gov/pubmed/32383312
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Abstract
Circadian disruption influences metabolic health. Metabolism modulates circadian function. However, the mechanisms coupling circadian rhythms and metabolism remain poorly understood. Here we report that Cystathionine beta-synthase (CBS), a central enzyme in one-carbon metabolism, functionally interacts with the core circadian protein Cryptochrome1 (CRY1). In cells, CBS augments CRY1 mediated repression of the CLOCK/BMAL1 complex and shortens circadian period. Notably, we find that mutant CBS-I278T protein, the most common cause of homocystinuria, does not bind CRY1 or regulate its repressor activity. Transgenic Cbs(Zn/Zn) mice, while maintaining circadian locomotor activity period, exhibit reduced circadian power and increased expression of E-BOX outputs. CBS function is reciprocally influenced by CRY1 binding. CRY1 modulates enzymatic activity of the CBS. Liver extracts from Cry1(-/-) mice show reduced CBS activity that normalizes after the addition of exogenous wild type (WT) CRY1. Metabolomic analysis of WT, Cbs(Zn/Zn) , Cry1(-/-) , and Cry2(-/-) samples highlights the metabolic importance of endogenous CRY1. We observed temporal variation in one-carbon and transsulfuration pathways attributable to CRY1 induced CBS activation. CBS-CRY1 binding provides a post-translational switch to modulate cellular circadian physiology and metabolic control.
Notes
1742-4658 Cal-Kayitmazbatir, Sibel Kulkoyluoglu-Cotul, Eylem Growe, Jacqueline Selby, Christopher P Rhoades, Seth D Malik, Dania Oner, Hasimcan Asimgil, Hande Francey, Lauren J Sancar, Aziz Kruger, Warren D Hogenesch, John B Weljie, Aalim Anafi, Ron C Kavakli, Ibrahim Halil R01 CA227485/CA/NCI NIH HHS/United States Journal Article England FEBS J. 2020 May 8. doi: 10.1111/febs.15360.