Just Published Paper

Our paper titled “Structure-based design and classifications of small molecules regulating the circadian rhythm period” is published in Scientific Reports. This work is done with collaboration wit Prof Metin Türkay.

Figure 1
Crystal structure of Cryptochrome 1(CRY1). There are two functionally important pockets, called primary and secondary pockets. Regions in primary and secondary pockets on CRY1 are shown in red color.


Serefs’ preprint paper is published on BioRxiv. This paper is entitled “Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice”  and describes discovery of a molecule, M47, selectively reduces half- life of mammalian Cryptochrome 1.

M47 enhanced the effect of oxaliplatin in p53 null mouse skin fibroblast (MSF) cells.

(A) Ras pT24 transformed p53 null MEF fibroblast cells were treated with 0, 10 or 20µM oxaliplatin and incubated for 24h. Then either DMSO or M47 was added and incubated for 16h. Cells were lysed and analyzed via protein immunoblot technique. At each cases M47 increases the cleaved PARP protein level and decreases CRY1 levels. Bar graph was drawn normalizing to 10µM dosage of oxaliplatin (Data represent the mean ± SEM, n=4 **: p < 0.005, versus DMSO control by two-way ANOVA). (B) M47 in p53−/−mice reduces age adjusted tumor incidence. Kaplan–Meier survival analysis (log-rank test) of the time of death with evidence of tumors showed significant differences between vehicle treated p53−/− and M47 treated p53−/− (**p<0,01)

Just Published Paper

Şeref’s paper titled “The Arg293 of Cryptochrome 1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm” is accepted to be published in Journal of Biological Chemistry.

This picture describes allosteric pathway between Arg293 and Ser-loop for binding of CLOCK/BMAL1.

Just Published Paper

Şeref’s paper titled “In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials” is accepted to be published in Journal of Biomolecular Structure and Dynamics.

The paper describes identification of well-tolerated and widely used drugs that have potential to be used against SARS-CoV-2

Just Published Paper

Our collaborative paper titled “Human CRY1 variants associate with attention deficit/hyperactivity disorder” where we functionally characterized CRY1-Delta6 is published in The Journal of Clinical Investigation.

Just Published Paper

Sibel’s paper titled “CRY1-CBS binding regulates circadian clock function and metabolism” is accepted to be published in The FEBS Journal.

This paper provide a novel insight that CBS-CRY1 binding provides a post-translational switch to modulate cellular circadian physiology and metabolic control.

The mechanisms coupling circadian rhythms and metabolism remain poorly understood. We find that the core circadian protein Cryptochrome 1 (CRY1) binds Cystathionine β-synthase (CBS), a central enzyme in one-carbon metabolism. This binding modulates the activity of both proteins. During the active phase, CBS augments CRY1 mediated repression of BMAL1/CLOCK driven transcription. During the rest phase, CRY1 increases CBS enzymatic activity.

Published Paper

Yağmur and Darya’s paper titled “A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude” is published in Journal of Biological Chemistry. 295(11):3518-3531

This paper describe the discovery of the small molecules has potential to be used as drug to eliminate circadian clock related diseases in ageing.

A schematic presentation of CLK8 affecting CLOCK and the circadian rhythm. CLOCK and BMAL1 are dynamically interacting. When CLK8 is present, it binds to CLOCK and reduces CLOCK and BMAL1 interaction. Upon binding of CLK8 to CLOCK, the translocation of the CLOCK into nucleus abolished. At the cellular level, CLK8 enhances the amplitude of the circadian rhythm. The role of CLOCK in regulating the circadian clock amplitude can be investigated using CLK8 to transiently modulate CLOCK. Thin line indicates reduction in strength of positive arm of TTFL while Thick line represent enhanced strength of negative arm of TTFL

Circadian Clock

Our laboratory is interested in understanding how clock works at cellular level. For more information please visit our research interest section. 

Almost every day, we wake up, get hungry, feel ourselves energetic or tired or succumb to sleep at the same hours. Although people may have different cycles, at certain hours of the day our bodies show the same responses. The circadian clock regulates the timing of sleep and wakefulness and, therefore, all dependent behavioural and physiological processes. In humans, a defect in the clock gene PER2 produces familial advanced sleep phase syndrome (FASPS); an analogous mutation causes the same phenotype in mice. People with a causal mutation in casein kinase CSNK1D and an associated variant in CSNK1E display ASPS and delayed sleep phase syndrome (DSPS), respectively. Finally, a human CLOCK variant is associated with diurnal sleep preference. Circadian clock genes are also associated with a host of neurological disorders including schizophrenia, unipolar major depression, and bipolar disorder.  Although it was widely believed that circadian clock disruption predisposes humans to cancer based largely on epidemiologic data, studies with Cry mutant mice revealed a more complex pattern of interactions among the clock, apoptosis, and oncogenic transformation.