Research Project: Biyolojik Saat Genlerinde Bulunan Snplerin Biyolojik Saat Üzerine Etkilerinin Moleküler Düzeyde İncelenmesi
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Contributors
Funders
ID
TB.00225
Authors
Barış, İbrahim
Teaching Faculty
Publications
Single nucleotide polymorphisms (SNPs) in circadian genes: impact on gene function and phenotype
(Academic Press Inc., 2023) Özcan, Onur; Barış, İbrahim; Kavaklı, İbrahim Halil; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Yes; College of Engineering; College of Sciences; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING
Circadian rhythm is an endogenous timing system that allows an organism to anticipate and adapt to daily changes and regulate various physiological variables such as the sleep-wake cycle. This rhythm is governed by a molecular circadian clock mechanism, generated by a transcriptional and translational feedback loop (TTFL) mechanism. In mammals, TTFL is determined by the interaction of four main clock proteins: BMAL1, CLOCK, Cryptochromes (CRY), and Periods (PER). BMAL1 and CLOCK form dimers and initiate the transcription of clock-controlled genes (CCG) by binding an E-box element with the promotor genes. Among CCGs, PERs and CRYs accumulate in the cytosol and translocate into the nucleus, where they interact with the BMAL1/CLOCK dimer and inhibit its activity. Several epidemiological and genetic studies have revealed that circadian rhythm disruption causes various types of disease. In this chapter, we summarize the effect of core clock gene SNPs on circadian rhythm and diseases in humans.
The Arg293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm
(American Society for Biochemistry and Molecular Biology (ASBMB), 2020) Barış, İbrahim; Gül, Şeref; Kavaklı, İbrahim Halil; Özcan, Onur; Sürme, Saliha; Gürkan, Berke; Aydın, Cihan; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Yes; College of Engineering; College of Sciences; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING
Mammalian circadian clocks are driven by transcription/ translation feedback loops composed of positive transcriptional activators (BMAL1 and CLOCK) and negative repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)). CRYs, in complex with PERs, bind to the BMAL1/CLOCK complex and repress E-box-driven transcription of clock-associated genes. There are two individual CRYs, with CRY1 exhibiting higher affinity to the BMAL1/CLOCK complex than CRY2. It is known that this differential binding is regulated by a dynamic serine-rich loop adjacent to the secondary pocket of both CRYs, but the underlying features controlling loop dynamics are not known. Here we report that allosteric regulation of the serine-rich loop is mediated by Arg-293 of CRY1, identified as a rare CRY1 SNP in the Ensembl and 1000 Genomes databases. The p.Arg293His CRY1 variant caused a shortened circadian period in a Cry1-/-Cry2-/-double knockout mouse embryonic fibroblast cell line. Moreover, the variant displayed reduced repressor activity on BMAL1/CLOCK driven transcription, which is explained by reduced affinity to BMAL1/ CLOCK in the absence of PER2 compared with CRY1.Molecular dynamics simulations revealed that the p.Arg293His CRY1 variant altered a communication pathway between Arg-293 and the serine loop by reducing its dynamicity. Collectively, this study provides direct evidence that allosterism in CRY1 is critical for the regulation of circadian rhythm.
