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Publication Open Access Association between gene polymorphisms in TIM1, TSLP, IL18R1 and childhood asthma in Turkish population(e-Century Publishing Corporation, 2014) Mete, Fatih; Özkaya, Emin; Aras, Şükrü; Köksal, Vedat; Etlik, Özdal; Department of Molecular Biology and Genetics; Barış, İbrahim; Teaching Faculty; Department of Molecular Biology and Genetics; College of Sciences; 111629Many immunologic and inflammatory mechanisms play a role in asthma etiology. The aim of this study was to investigate the susceptibility of asthma patients in the Turkish population with demonstrating genes for polymorphisms in TIM1, TSLP and IL18R1. All of the genomic DNA samples were isolated from blood samples according to a standard salting-out protocol. DNA samples were stored at -20 degrees C until the genotype analysis was performed. rs3806933 (TSLP -847 C > T) and TIM1 -416G > C were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The rs3806933 (TSLP -847 C > T) was genotyped by PCR using our new primers and HphI restriction enzyme digestion. rs2287033 (IL18R1 c. 1270+150 A > G), rs3213733 (IL18R1 c. 626-196 G > T), and rs3771166 (IL18R1-c. 302+1694 C > T) were genotyped using SYBR green dye based real time PCR assay. Results: The allele frequencies of 5 SNPs in TSLP, TIM-1, and IL18R1 genes were determined in 139 asthmatic patients and 126 healthy controls of in Turkish population. The investigated SNPs are as follows; rs3806933 (TSLP -847 C > T), TIM1 -416G > C, rs2287033 (IL18R1 c. 1270+150 A > G), rs3213733 (IL18R1 c. 626-196 G > T), and rs3771166 (IL18R1-c. 302+1694 C > T). Results suggest that IL18R1 c. 626-196 G > T (rs3213733) and TIM1 -416G > C are significantly associated with asthma in patients in Turkish population. Patients with AA genotypes of rs2287033 (IL18R1 c. 1270+150 A > G), have significantly less total serum IgE levels when compared with patients having GG or GA genotypes (p < 0.012; 381.77 +/- 239.46 vs 557.52 +/- 549.96, respectively). Conclusion: This study showed that IL18R1 c. 626 -196 G > T (rs3213733) and TIM1 -416G > C are significantly associated with asthma patients in Turkish population.Publication Open Access Deletion of conserved protein phosphatases reverses defects associated with mitochondrial DNA damage in Saccharomyces cerevisiae(National Academy of Sciences, 2014) Department of Molecular Biology and Genetics; Garipler, Görkem; Mutlu, Nebibe; Lack, Nathan Alan; Dunn, Cory David; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; School of Medicine; Graduate School of Sciences and Engineering; N/A; N/A; 120842; N/AMitochondrial biogenesis is regulated by signaling pathways sensitive to extracellular conditions and to the internal environment of the cell. Therefore, treatments for disease caused by mutation of mtDNA may emerge from studies of how signal transduction pathways command mitochondrial function. We have examined the role of phosphatases under the control of the conserved alpha 4/Tap42 protein in cells lacking a mitochondrial genome. We found that deletion of protein phosphatase 2A (PP2A) or of protein phosphatase 6 (PP6) protects cells from the reduced proliferation, mitochondrial protein import defects, lower mitochondrial electrochemical potential, and nuclear transcriptional response associated with mtDNA damage. Moreover, PP2A or PP6 deletion allows viability of a sensitized yeast strain after mtDNA loss. Interestingly, the Saccharomyces cerevisiae ortholog of the mammalian AMP-activated protein kinase was required for the full benefits of PP6 deletion and also for proliferation of otherwise wild-type cells lacking mtDNA. Our work highlights the important role that nutrient-responsive signaling pathways can play in determining the response to mitochondrial dysfunction.Publication Open Access Mitochondrial dysfunction plus high-sugar diet provokes a metabolic crisis that inhibits growth(Public Library of Science, 2016) Kemppainen, Esko; George, Jack; Garipler, Görkem; Tuomela, Tea; Kiviranta, Essi; Soga, Tomoyoshi; Jacobs, Howard T.; Department of Molecular Biology and Genetics; Dunn, Cory David; Faculty Member; Department of Molecular Biology and Genetics; College of SciencesThe Drosophila mutant tko(25t) exhibits a deficiency ofmitochondrial protein synthesis, leading to a global insufficiency of respiration and oxidative phosphorylation. This entrains an organismal phenotype of developmental delay and sensitivity to seizures induced bymechanical stress. We found that the mutant phenotype is exacerbated in a dose-dependent fashion by high dietary sugar levels. tko(25t) larvae were found to exhibit severe metabolic abnormalities that were further accentuated by high-sugar diet. These include elevated pyruvate and lactate, decreased ATP and NADPH. Dietary pyruvate or lactate supplementation phenocopied the effects of high sugar. Based on tissue-specific rescue, the crucial tissue in which this metabolic crisis initiates is the gut. It is accompanied by down-regulation of the apparatus of cytosolic protein synthesis and secretion at both the RNA and post-translational levels, including a novel regulation of S6 kinase at the protein level.Publication Open 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; 40319Mammalian 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.Publication Open Access The centriolar satellite protein CCDC66 interacts with CEP290 and functions in cilium formation and trafficking(The Company of Biologists (United Kingdom), 2017) Rauniyar, Navin; Yates, John R., III; Department of Molecular Biology and Genetics; Karalar, Elif Nur Fırat; Çonkar, Deniz; Culfa, Efraim; Odabaşı, Ezgi; PhD Student; Master Student; Other; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; 206349; N/A; N/A; N/ACentriolar satellites are membrane-less structures that localize and move around the centrosome and cilium complex in a microtubule-dependent manner. They play important roles in centrosome- and cilium-related processes, including protein trafficking to the centrosome and cilium complex, and ciliogenesis, and they are implicated in ciliopathies. Despite the important regulatory roles of centriolar satellites in the assembly and function of the centrosome and cilium complex, the molecular mechanisms of their functions remain poorly understood. To dissect the mechanism for their regulatory roles during ciliogenesis, we performed an analysis to determine the proteins that localize in close proximity to the satellite protein CEP72, among which was the retinal degeneration gene product CCDC66. We identified CCDC66 as a microtubule-associated protein that dynamically localizes to the centrosome, centriolar satellites and the primary cilium throughout the cell cycle. Like the bbsome component BBS4, CCDC66 distributes between satellites and the primary cilium during ciliogenesis. CCDC66 has extensive proximity interactions with centrosome and centriolar satellite proteins, and co-immunoprecipitation experiments revealed interactions between CCDC66, CEP290 and PCM1. Ciliogenesis, ciliary recruitment of BBS4 and centriolar satellite organization are impaired in cells depleted for CCDC66. Taken together, our findings identify CCDC66 as a targeting factor for centrosome and cilium proteins.
Publication Metadata only The long and winding road of reprogramming-induced rejuvenation(Nature Portfolio, 2024) Gladyshev, Vadim N.; Department of Molecular Biology and Genetics; Yücel, Ali Doğa; Department of Molecular Biology and Genetics; ; College of Sciences;Organismal aging is inherently connected to the aging of its constituent cells and systems. Reducing the biological age of the organism may be assisted by reducing the age of its cells - an approach exemplified by partial cell reprogramming through the expression of Yamanaka factors or exposure to chemical cocktails. It is crucial to protect cell type identity during partial reprogramming, as cells need to retain or rapidly regain their functions following the treatment. Another critical issue is the ability to quantify biological age as reprogrammed older cells acquire younger states. We discuss recent advances in reprogramming-induced rejuvenation and offer a critical review of this procedure and its relationship to the fundamental nature of aging. We further comparatively analyze partial reprogramming, full reprogramming and transdifferentiation approaches, assess safety concerns and emphasize the importance of distinguishing rejuvenation from dedifferentiation. Finally, we highlight translational opportunities that the reprogramming-induced rejuvenation approach offers. Rejuvenation and partial reprogramming are two frontier areas in the field of aging. Here, the authors summarize advances in these fields and suggest future directions for research and therapy.