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Roles of OGG1 in transcriptional regulation and maintenance of metabolic homeostasis.

ABSTRACT: Cellular damage produced by conditions generating oxidative stress have far-reaching implications in human disease that encompass, but are not restricted to aging, cardiovascular disease, type 2 diabetes, airway inflammation/asthma, cancer, and metabolic syndrome including visceral obesity, insulin resistance, fatty liver disease, and dyslipidemia. Although there are numerous sources and cellular targets of oxidative stress, this review will highlight literature that has investigated downstream consequences of oxidatively-induced DNA damage in both nuclear and mitochondrial genomes. The presence of such damage can in turn, directly and indirectly modulate cellular transcriptional and repair responses to such stressors. As such, the persistence of base damage can serve as a key regulator in coordinated gene-response cascades. Conversely, repair of these DNA lesions serves as both a suppressor of mutagenesis and by inference carcinogenesis, and as a signal for the cessation of ongoing oxidative stress. A key enzyme in all these processes is 8-oxoguanine DNA glycosylase (OGG1), which, via non-catalytic binding to oxidatively-induced DNA damage in promoter regions, serves as a nucleation site around which changes in large-scale regulation of inflammation-associated gene expression can occur. Further, the catalytic function of OGG1 can alter the three-dimensional structure of specialized DNA sequences, leading to changes in transcriptional profiles. This review will concentrate on adverse deleterious health effects that are associated with both the diminution of OGG1 activity via population-specific polymorphic variants and the complete loss of OGG1 in murine models. This mouse model displays diet- and age-related induction of metabolic syndrome, highlighting a key role for OGG1 in protecting against these phenotypes. Conversely, recent investigations using murine models having enhanced global expression of a mitochondrial-targeted OGG1 demonstrate that they are highly resistant to diet-induced disease. These data suggest strategies through which therapeutic interventions could be designed for reducing or limiting adverse human health consequences to these ubiquitous stressors.

SUBMITTER: Sampath H

PROVIDER: S-EPMC6939861 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Roles of OGG1 in transcriptional regulation and maintenance of metabolic homeostasis.

Sampath Harini H Lloyd R Stephen RS

DNA repair 20190708

Cellular damage produced by conditions generating oxidative stress have far-reaching implications in human disease that encompass, but are not restricted to aging, cardiovascular disease, type 2 diabetes, airway inflammation/asthma, cancer, and metabolic syndrome including visceral obesity, insulin resistance, fatty liver disease, and dyslipidemia. Although there are numerous sources and cellular targets of oxidative stress, this review will highlight literature that has investigated downstream ...[more]

PMID: 31311771

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Project description:Plant hormones cytokinins (CKs) are one of the major mediators of physiological responses throughout plant life span. Therefore, a proper homeostasis is maintained by regulation of their active levels. Besides degradation, CKs are deactivated by uridine diphosphate glycosyltransferases (UGTs). Physiologically, CKs active levels decline in senescing organs, providing a signal to nutrients that a shift to reproductive tissues has begun. In this work, we show CK glucosides distribution in Arabidopsis leaves during major developmental transition phases. Besides continuous accumulation of N-glucosides we detected sharp maximum of the glucosides in senescence. This is caused prevalently by N7-glucosides followed by N9-glucosides and specifically also by trans-zeatin-O-glucoside (tZOG). Interestingly, we observed a similar trend in response to exogenously applied CK. In Arabidopsis, only three UGTs deactivate CKs in vivo: UGT76C1, UGT76C2 and UGT85A1. We thereby show that UGT85A1 is specifically expressed in senescent leaves whereas UGT76C2 is activated rapidly in response to exogenously applied CK. To shed more light on the UGTs physiological roles, we performed a comparative study on UGTs loss-of-function mutants, characterizing a true ugt85a1-1 loss-of-function mutant for the first time. Although no altered phenotype was detected under standard condition we observed reduced chlorophyll degradation with increased anthocyanin accumulation in our experiment on detached leaves accompanied by senescence and stress related genes modulated expression. Among the mutants, ugt76c2 possessed extremely diminished CK N-glucosides levels whereas ugt76c1 showed some specificity toward cis-zeatin (cZ). Besides tZOG, a broader range of CK glucosides was decreased in ugt85a1-1. Performing CK metabolism gene expression profiling, we revealed that activation of CK degradation pathway serves as a general regulatory mechanism of disturbed CK homeostasis followed by decreased CK signaling in all UGT mutants. In contrast, a specific regulation of CKX7, CKX1 and CKX2 was observed for each individual UGT mutant isoform after exogenous CK uptake. Employing an in silico prediction we proposed cytosolic localization of UGT76C1 and UGT76C2, that we further confirmed by GFP tagging of UGT76C2. Integrating all the results, we therefore hypothesize that UGTs possess different physiological roles in Arabidopsis and serve as a fine-tuning mechanism of active CK levels in cytosol.

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Roles of OGG1 in transcriptional regulation and maintenance of metabolic homeostasis.

Publications

Roles of OGG1 in transcriptional regulation and maintenance of metabolic homeostasis.

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