scholarly journals UHRF1 suppresses retrotransposons and cooperates with PRMT5 and PIWI proteins in male germ cells

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Juan Dong ◽  
Xiaoli Wang ◽  
Congcong Cao ◽  
Yujiao Wen ◽  
Akihiko Sakashita ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Histone Modification ◽  
Dna Damage Response ◽  
Germ Cells ◽  
Dna Hypomethylation ◽  
Male Germ Cells ◽  
Arginine Methyltransferase ◽  
Male Germline ◽  
Damage Response

Abstract DNA methylation, repressive histone marks, and PIWI-interacting RNA (piRNA) are essential for the control of retrotransposon silencing in the mammalian germline. However, it remains unknown how these repressive epigenetic pathways crosstalk to ensure retrotransposon silencing in the male germline. Here, we show that UHRF1 is responsible for retrotransposon silencing and cooperates with repressive epigenetic pathways in male germ cells. Conditional loss of UHRF1 in postnatal germ cells causes DNA hypomethylation, upregulation of retrotransposons, the activation of a DNA damage response, and switches in the global chromatin status, leading to complete male sterility. Furthermore, we show that UHRF1 interacts with PRMT5, an arginine methyltransferase, to regulate the repressive histone arginine modifications (H4R3me2s and H3R2me2s), and cooperates with the PIWI pathway during spermatogenesis. Collectively, UHRF1 regulates retrotransposon silencing in male germ cells and provides a molecular link between DNA methylation, histone modification, and the PIWI pathway in the germline.

scholarly journals Histone Modification Is Involved in Okadaic Acid (OA) Induced DNA Damage Response and G2-M Transition Arrest in Maize

PLoS ONE ◽  
2016 ◽  
Vol 11 (5) ◽  
pp. e0155852 ◽  
Author(s):  
Hao Zhang ◽  
Pu Wang ◽  
Haoli Hou ◽  
Huan Wen ◽  
Hong Zhou ◽  
...  
Keyword(s):  
Dna Damage ◽  
Histone Modification ◽  
Dna Damage Response ◽  
Okadaic Acid ◽  
Damage Response

scholarly journals DNA Methylation Inhibitor 5-Aza-2′-Deoxycytidine Induces Reversible Genome-Wide DNA Damage That Is Distinctly Influenced by DNA Methyltransferases 1 and 3B

2007 ◽  
Vol 28 (2) ◽  
pp. 752-771 ◽  
Author(s):  
Stela S. Palii ◽  
Beth O. Van Emburgh ◽  
Umesh T. Sankpal ◽  
Kevin D. Brown ◽  
Keith D. Robertson
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Tumor Cells ◽  
Dna Damage Response ◽  
Dna Methyltransferases ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Checkpoint Kinase ◽  
Genome Wide ◽  
Damage Response

ABSTRACT Genome-wide DNA methylation patterns are frequently deregulated in cancer. There is considerable interest in targeting the methylation machinery in tumor cells using nucleoside analogs of cytosine, such as 5-aza-2′-deoxycytidine (5-azadC). 5-azadC exerts its antitumor effects by reactivation of aberrantly hypermethylated growth regulatory genes and cytoxicity resulting from DNA damage. We sought to better characterize the DNA damage response of tumor cells to 5-azadC and the role of DNA methyltransferases 1 and 3B (DNMT1 and DNMT3B, respectively) in modulating this process. We demonstrate that 5-azadC treatment results in growth inhibition and G2 arrest—hallmarks of a DNA damage response. 5-azadC treatment led to formation of DNA double-strand breaks, as monitored by formation of γ-H2AX foci and comet assay, in an ATM (ataxia-telangiectasia mutated)-dependent manner, and this damage was repaired following drug removal. Further analysis revealed activation of key strand break repair proteins including ATM, ATR (ATM-Rad3-related), checkpoint kinase 1 (CHK1), BRCA1, NBS1, and RAD51 by Western blotting and immunofluorescence. Significantly, DNMT1-deficient cells demonstrated profound defects in these responses, including complete lack of γ-H2AX induction and blunted p53 and CHK1 activation, while DNMT3B-deficient cells generally showed mild defects. We identified a novel interaction between DNMT1 and checkpoint kinase CHK1 and showed that the defective damage response in DNMT1-deficient cells is at least in part due to altered CHK1 subcellular localization. This study therefore greatly enhances our understanding of the mechanisms underlying 5-azadC cytotoxicity and reveals novel functions for DNMT1 as a component of the cellular response to DNA damage, which may help optimize patient responses to this agent in the future.

scholarly journals Somatic Niche Cells Regulate the CEP-1/p53-Mediated DNA Damage Response in Primordial Germ Cells

2019 ◽  
Vol 50 (2) ◽  
pp. 167-183.e8 ◽  
Author(s):  
Hui-Ling Ou ◽  
Christine S. Kim ◽  
Simon Uszkoreit ◽  
Sara A. Wickström ◽  
Björn Schumacher
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Germ Cells ◽  
Primordial Germ Cells ◽  
Damage Response

scholarly journals 180. THE CONSEQUENCES OF ACRYLAMIDE EXPOSURE ON THE MALE GERMLINE

2010 ◽  
Vol 22 (9) ◽  
pp. 98
Author(s):  
B. J. Nixon ◽  
B. Nixon ◽  
S. D. Roman
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Cytochrome P450 ◽  
Germ Cells ◽  
Dietary Exposure ◽  
Cytochrome P450 Enzymes ◽  
Male Germ Cells ◽  
P450 Gene ◽  
Male Germline ◽  
Future Outcomes

Acrylamide is a common industrial compound that has recently been identified in cooked, carbohydrate-rich foods such as potato chips, breads and cereals. Acrylamide has been found to be a reproductive toxin in rodents, eliciting male infertility and transgenerational toxicity through the male germline; thus dietary exposure to the compound may have consequences for male fertility and reproduction in humans. The aim of this project was to elucidate the mechanisms of acrylamide toxicity in male germ cells of mice. Freshly isolated early male germ cells were exposed to acrylamide and assessed for cell viability and aberrant morphology. DNA damage in these cells was also investigated using a modified version of the Comet Assay, which allows for adduct specificity. Significant increases in cell death or aberrant morphology were not observed following acrylamide exposure (1 µM, 18 hours). However, a significant increase in DNA damage (125% increase in mean tail DNA assessed by Comet) was identified; which may originate from either the metabolic conversion of acrylamide to glycidamide, leading to glycidamide adducts, or from oxidative stress. Additionally, the regulation of cytochrome P450 gene expression was measured using real time PCR and early male germ cells were found to upregulate gene expression of cytochrome P450 enzymes in response to acrylamide exposure. Collectively, these results support a genotoxic mode of action of acrylamide toxicity, in addition to potential oxidative damage in male germ cells. However, the mechanism by which acrylamide elicits toxicity in germ cells requires further investigation. Future outcomes of this research may provide insight into factors necessary for the healthy development of offspring and aid in the risk assessment of dietary acrylamide exposure in humans.

DNA methylation changes induced by BDE-209 are related to DNA damage response and germ cell development in GC-2spd

2021 ◽  
Vol 109 ◽  
pp. 161-170
Author(s):  
Xiangyang Li ◽  
Yue Zhang ◽  
Xiaomin Dong ◽  
Guiqing Zhou ◽  
Yujian Sang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Germ Cell ◽  
Dna Damage Response ◽  
Cell Development ◽  
Germ Cell Development ◽  
Damage Response ◽  
Bde 209
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