scholarly journals Mitochondrial fatty acid utilization increases chromatin oxidative stress in cardiomyocytes

2021 ◽  
Vol 118 (34) ◽  
pp. e2101674118
Author(s):  
Ivan Menendez-Montes ◽  
Salim Abdisalaam ◽  
Feng Xiao ◽  
Nicholas T. Lam ◽  
Shibani Mukherjee ◽  
...  
Keyword(s):  
Dna Damage ◽  
Fatty Acid ◽  
Oxidative Dna Damage ◽  
Redox Status ◽  
Neonatal Rat ◽  
Prooxidant Effect ◽  
Nuclear Lamin ◽  
Mitochondrial Fatty Acid ◽  
Short Period ◽  
Damage Response

The inability of adult mammalian cardiomyocytes to proliferate underpins the development of heart failure following myocardial injury. Although the newborn mammalian heart can spontaneously regenerate for a short period of time after birth, this ability is lost within the first week after birth in mice, partly due to increased mitochondrial reactive oxygen species (ROS) production which results in oxidative DNA damage and activation of DNA damage response. This increase in ROS levels coincides with a postnatal switch from anaerobic glycolysis to fatty acid (FA) oxidation by cardiac mitochondria. However, to date, a direct link between mitochondrial substrate utilization and oxidative DNA damage is lacking. Here, we generated ROS-sensitive fluorescent sensors targeted to different subnuclear compartments (chromatin, heterochromatin, telomeres, and nuclear lamin) in neonatal rat ventricular cardiomyocytes, which allowed us to determine the spatial localization of ROS in cardiomyocyte nuclei upon manipulation of mitochondrial respiration. Our results demonstrate that FA utilization by the mitochondria induces a significant increase in ROS detection at the chromatin level compared to other nuclear compartments. These results indicate that mitochondrial metabolic perturbations directly alter the nuclear redox status and that the chromatin appears to be particularly sensitive to the prooxidant effect of FA utilization by the mitochondria.

scholarly journals In Barrett’s epithelial cells, weakly acidic bile salt solutions cause oxidative DNA damage with response and repair mediated by p38

2020 ◽  
Vol 318 (3) ◽  
pp. G464-G478
Author(s):  
Xiaofang Huo ◽  
Kerry B. Dunbar ◽  
Xi Zhang ◽  
Qiuyang Zhang ◽  
Stuart Jon Spechler ◽  
...  
Keyword(s):  
Dna Damage ◽  
Bile Salt ◽  
Barrett’S Esophagus ◽  
Esophageal Adenocarcinoma ◽  
Dna Damage Response ◽  
Barrett's Esophagus ◽  
Oxidative Dna Damage ◽  
Damage Response ◽  
Barrett's Metaplasia ◽  
Barrett’S Metaplasia

The frequency of esophageal adenocarcinoma is rising despite widespread use of proton pump inhibitors (PPIs), which heal reflux esophagitis but do not prevent reflux of weakly acidic gastric juice and bile in Barrett’s esophagus patients. We aimed to determine if weakly acidic (pH 5.5) bile salt medium (WABM) causes DNA damage in Barrett’s cells. Because p53 is inactivated frequently in Barrett’s esophagus and p38 can assume p53 functions, we explored p38’s role in DNA damage response and repair. We exposed Barrett’s cells with or without p53 knockdown to WABM, and evaluated DNA damage, its response and repair, and whether these effects are p38 dependent. We also measured phospho-p38 in biopsies of Barrett’s metaplasia exposed to deoxycholic acid (DCA). WABM caused phospho-H2AX increases that were blocked by a reactive oxygen species (ROS) scavenger. WABM increased phospho-p38 and reduced bromodeoxyuridine incorporation (an index of S phase entry). Repair of WABM-induced DNA damage proceeded through p38-mediated base excision repair (BER) associated with reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease I (Ref-1/APE1). Cells treated with WABM supplemented with ursodeoxycholic acid (UDCA) exhibited enhanced p38-mediated responses to DNA damage. All of these effects were observed in p53-intact and p53-deficient Barrett’s cells. In patients, esophageal DCA perfusion significantly increased phospho-p38 in Barrett’s metaplasia. WABM exposure generates ROS, causing oxidative DNA damage in Barrett’s cells, a mechanism possibly underlying the rising frequency of esophageal adenocarcinoma despite PPI usage. p38 plays a central role in oxidative DNA damage response and Ref-1/APE1-associated BER, suggesting potential chemopreventive roles for agents like UDCA that increase p38 activity in Barrett’s esophagus. NEW & NOTEWORTHY We found that weakly acidic bile salt solutions, with compositions similar to the refluxed gastric juice of gastroesophageal reflux disease patients on proton pump inhibitors, cause oxidative DNA damage in Barrett’s metaplasia that could contribute to the development of esophageal adenocarcinoma. We also have elucidated a critical role for p38 in Barrett’s metaplasia in its response to and repair of oxidative DNA damage, suggesting a potential chemopreventive role for agents like ursodeoxycholic acid that increase p38 activity in Barrett’s esophagus.

scholarly journals Werner Protein Protects Nonproliferating Cells from Oxidative DNA Damage

2005 ◽  
Vol 25 (23) ◽  
pp. 10492-10506 ◽  
Author(s):  
Anna M. Szekely ◽  
Franziska Bleichert ◽  
Astrid Nümann ◽  
Stephen Van Komen ◽  
Elisabeth Manasanch ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Oxidative Dna Damage ◽  
Werner Syndrome ◽  
Human Fibroblasts ◽  
Telomere Maintenance ◽  
Telomere Binding Protein ◽  
Damage Response ◽  
Dividing Cells

ABSTRACT Werner syndrome, caused by mutations of the WRN gene, mimics many changes of normal aging. Although roles for WRN protein in DNA replication, recombination, and telomere maintenance have been suggested, the pathology of rapidly dividing cells is not a feature of Werner syndrome. To identify cellular events that are specifically vulnerable to WRN deficiency, we used RNA interference (RNAi) to knockdown WRN or BLM (the RecQ helicase mutated in Bloom syndrome) expression in primary human fibroblasts. Withdrawal of WRN or BLM produced accelerated cellular senescence phenotype and DNA damage response in normal fibroblasts, as evidenced by induction of γH2AX and 53BP1 nuclear foci. After WRN depletion, the induction of these foci was seen most prominently in nondividing cells. Growth in physiological (3%) oxygen or in the presence of an antioxidant prevented the development of the DNA damage foci in WRN-depleted cells, whereas acute oxidative stress led to inefficient repair of the lesions. Furthermore, WRN RNAi-induced DNA damage was suppressed by overexpression of the telomere-binding protein TRF2. These conditions, however, did not prevent the DNA damage response in BLM-ablated cells, suggesting a distinct role for WRN in DNA homeostasis in vivo. Thus, manifestations of Werner syndrome may reflect an impaired ability of slowly dividing cells to limit oxidative DNA damage.

scholarly journals The CHD6 chromatin remodeler is an oxidative DNA damage response factor

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Shaun Moore ◽  
N. Daniel Berger ◽  
Martijn S. Luijsterburg ◽  
Cortt G. Piett ◽  
Fintan K. T. Stanley ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Oxidative Dna Damage ◽  
Response Factor ◽  
Chromatin Remodeler ◽  
Damage Response

CHK2-mediated regulation of PARP1 in oxidative DNA damage response

Oncogene ◽  
2018 ◽  
Vol 38 (8) ◽  
pp. 1166-1182 ◽  
Author(s):  
Pei-Ching Hsu ◽  
Rajaneesh Karimpurath Gopinath ◽  
Yi-An Hsueh ◽  
Sheau-Yann Shieh
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Oxidative Dna Damage ◽  
Damage Response

scholarly journals Sustained Activation of TNFα-Induced DNA Damage Response in Newly Differentiated Adipocytes

2021 ◽  
Vol 22 (19) ◽  
pp. 10548
Author(s):  
Mahara Valverde ◽  
Aarón Sánchez-Brito
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Oxidative Dna Damage ◽  
Human Adipose Tissue ◽  
Repair Capacity ◽  
Disease States ◽  
Gradual Loss ◽  
Damage Response ◽  
Stress Signals ◽  
The Impact

The response to DNA damage is the mechanism that allows the interaction between stress signals, inflammatory secretions, DNA repair, and maintenance of cell and tissue homeostasis. Adipocyte dysfunction is the cellular trigger for various disease states such as insulin resistance, diabetes, and obesity, among many others. Previously, our group demonstrated that adipogenesis per se, from mesenchymal/stromal stem cells derived from human adipose tissue (hASCs), involves an accumulation of DNA damage and a gradual loss of the repair capacity of oxidative DNA damage. Therefore, our objective was to identify whether healthy adipocytes differentiated for the first time from hASCs, when receiving inflammatory signals induced with TNFα, were able to persistently activate the DNA Damage Response and thus trigger adipocyte dysfunction. We found that TNFα at similar levels circulating in obese humans induce a sustained response to DNA damage response as part of the Senescence-Associated Secretory Phenotype. This mechanism shows the impact of inflammatory environment early affect adipocyte function, independently of aging.

scholarly journals Smoking-promoted oxidative DNA damage response is highly correlated to lung carcinogenesis

Oncotarget ◽  
2016 ◽  
Vol 7 (14) ◽  
pp. 18919-18926 ◽  
Author(s):  
Chao Cao ◽  
Tianwen Lai ◽  
Miao Li ◽  
Hongbin Zhou ◽  
Dan Lv ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Oxidative Dna Damage ◽  
Lung Carcinogenesis ◽  
Damage Response ◽  
Highly Correlated
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