Researcher:
Özcan, Onur

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PhD Student

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Onur

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Özcan

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Özcan, Onur

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2020 - 20226

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Researcher Of Publications: search.filters.isAuthorOfPublication.4dd21707-8aca-4502-8b57-164c799405aa

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    Allosteric regulation of CRYs in mammalian circadian clock
    (Elsevier B.V., 2021) N/A; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; N/A; Kavaklı, İbrahim Halil; Gül, Şeref; Özcan, Onur; Faculty Member; Researcher; PhD Student; Department of Chemical and Biological Engineering; College of Engineering; College of Engineering; Graduate School of Sciences and Engineering; 40319; N/A; N/A
    Mammalian circadian clocks are composed of transcriptional-translational feedback loops. Transcriptional activators (BMAL1/CLOCK) form positive arm and transcriptional repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)) form the negative arm of the clock mechanism in mammals. CRYs have conserved primary (FAD binding) and secondary pockets critical to interact with different proteins. Despite high structural similarities between CRY1 and CRY2, studies suggest each CRY plays a different role in the circadian clock. For example, the binding of the CRY1 to CLOCK is regulated by a dynamic serine-rich loop (Ser-loop) around the secondary pocket. A recent report showed that a distant residue Arg-293 allosterically regulates the Ser-loop in CRY1. Here, using molecular dynamics simulations, we showed that Arg-311 to His mutation in CRY2 (homolog of Arg-293 of CRY1) had a minor effect on the allosteric path to Ser-loop.
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    Transcriptome analysis of the circadian clock gene bmal1 deletion with opposite carcinogenic effects
    (Springer Heidelberg, 2021) Emisoglu-Kulahli, Handan; Morgil, Hande; Aygenli, Fatih; Selvi, Saba; Ozturk, Nuri; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; N/A; Gül, Şeref; Kavaklı, İbrahim Halil; Özcan, Onur; Researcher; Faculty Member; N/A; Department of Chemical and Biological Engineering; College of Engineering; College of Engineering; N/A; N/A; 40319; N/A
    We have previously reported that the deletion of BMAL1 gene has opposite effects in respect to its contribution to the pathways that are effective in the multistage carcinogenesis process. BMAL1 deletion sensitized nearly normal breast epithelial (MCF10A) and invasive breast cancer cells (MDA-MB-231) to cisplatin- and doxorubicin-induced apoptosis, while this deletion also aggravated the invasive potential of MDA-MB-231 cells. However, the mechanistic relationship of the seemingly opposite contribution of BMAL1 deletion to carcinogenesis process is not known at genome-wide level. In this study, an RNA-seq approach was taken to uncover the differentially expressed genes (DEGs) and pathways after treating BMAL1 knockout (KO) or wild-type (WT) MDA-MB-231 cells with cisplatin and doxorubicin to initiate apoptosis. Gene set enrichment analysis with the DEGs demonstrated that enrichment in multiple genes/pathways contributes to sensitization to cisplatin- or doxorubicin-induced apoptosis in BMAL1-dependent manner. Additionally, our DEG analysis suggested that non-coding transcript RNA (such as lncRNA and processed pseudogenes) may have role in cisplatin- or doxorubicin-induced apoptosis. Protein-protein interaction network obtained from common DEGs in cisplatin and doxorubicin treatments revealed that GSK3 beta, NACC1, and EGFR are the principal genes regulating the response of the KO cells. Moreover, the analysis of DEGs among untreated BMAL1 KO and WT cells revealed that epithelial-mesenchymal transition genes are up-regulated in KO cells. As a negative control, we have also analyzed the DEGs following treatment with an endoplasmic reticulum (ER) stress-inducing agent, tunicamycin, which was affected by BMAL1 deletion minimally. Collectively, the present study suggests that BMAL1 regulates many genes/pathways of which the alteration in BMAL1 KO cells may shed light on pleotropic phenotype observed.
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    PublicationOpen Access
    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
    (Taylor _ Francis, 2020) Asar, Sinan; Okyar, Alper; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Gül, Şeref; Özcan, Onur; Barış, İbrahim; Kavaklı, İbrahim Halil; Researcher; Teaching Faculty; Faculty Member; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; N/A; N/A; 111629; 40319
    Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxychloroquine. Therefore, the repurposing of clinically approved drugs for use against SARS-CoV-2 has become a viable strategy. Here, we searched for drugs that target SARS-CoV-2 3C-like protease (3CL(pro)) and viral RNA-dependent RNA polymerase (RdRp) by in silico screening of the U.S. Food and Drug Administration approved drug library. Well-tolerated and widely used drugs were selected for molecular dynamics (MD) simulations to evaluate drug-protein interactions and their persistence under physiological conditions. Tetracycline, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone formed stable interactions with 3CL(pro)based on MD simulation results. Similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan bound to the enzyme with high binding free energies. Docking results suggest that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. As these drugs are well tolerated, cost-effective, and widely used, our study suggests that they could potentially to be used in clinical trials for the treatment of SARS-CoV-2-infected patients.
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    PublicationOpen Access
    Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice
    (Nature Portfolio, 2022) Akyel, Yasemin Kübra; Korkmaz, Tuba; Selvi, Saba; Danış, İbrahim; İpek, Özgecan Savluğ; Aygenli, Fatih; Öztürk, Nuri; Öztürk, Narin; Ünal, Durişehvar Özer; Güzel, Mustafa; Okyar, Alper; N/A; Department of Chemical and Biological Engineering; Department of Industrial Engineering; Gül, Şeref; Gül, Zeynep Melis; Işın, Şafak; Özcan, Onur; Akarlar, Büşra; Taşkın, Ali Cihan; Türkay, Metin; Kavaklı, İbrahim Halil; Researcher; Other; Faculty Member; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Industrial Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Engineering; N/A; N/A; N/A; N/A; N/A; 291296; 105301; 24956; 40319
    Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis. Here, we discovered a molecule (M47) that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The M47 selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and resulted in increasing the circadian period length of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 increased degradation of the CRY1 in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced oxaliplatin-induced apoptosis in Ras-transformed p53 null fibroblast cells. Systemic repetitive administration of M47 increased the median lifespan of p53(-/-) mice by similar to 25%. Collectively our data suggest that M47 is a promising molecule to treat forms of cancer depending on the p53 mutation.
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    PublicationOpen Access
    The secondary pocket of cryptochrome 2 is important for the regulation of its stability and localization
    (Elsevier, 2022) Gül, Şeref; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Kavaklı, İbrahim Halil; Barış, İbrahim; Özcan, Onur; Faculty Member; Teaching Faculty; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; College of Engineering; Graduate School of Sciences and Engineering; 40319; 111629; N/A; N/A; N/A
    Human clock-gene variations contribute to the phenotypic differences observed in various behavioral and physiological processes, such as diurnal preference, sleep, metabolism, mood regulation, addiction, and fertility. However, little is known about the possible effects of identified variations at the molecular level. In this study, we performed a functional characterization at the cellular level of rare cryptochrome 2 (CRY2) missense variations that were identified from the Ensembl database. Our structural studies revealed that three variations (p.Pro123Leu, p.Asp406His, and p.Ser410Ile) are located at the rim of the secondary pocket of CRY2. We show that these variants were unable to repress CLOCK (circadian locomotor output cycles kaput)/BMAL1 (brain and muscle ARNT-like-1)-driven transcription in a cell-based reporter assay and had reduced affinity to CLOCK-BMAL1. Furthermore, our biochemical studies indicated that the variants were less stable than the WT CRY2, which could be rescued in the presence of period 2 (PER2), another core clock protein. Finally, we found that these variants were unable to properly localize to the nucleus and thereby were unable to rescue the circadian rhythm in a Cry1(-/-)Cry2(-/-) double KO mouse embryonic fibroblast cell line. Collectively, our data suggest that the rim of the secondary pocket of CRY2 plays a significant role in its nuclear localization independently of PER2 and in the intact circadian rhythm at the cellular level.
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    PublicationOpen Access
    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) Aydın, Cihan; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Gül, Şeref; Özcan, Onur; Gürkan, Berke; Sürme, Saliha; Barış, İbrahim; Kavaklı, İbrahim Halil; Researcher; Teaching Faculty; Teaching Faculty; Faculty Member; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; N/A; N/A; N/A; N/A; 111629; 40319
    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.