scholarly journals Novel epigenetic signature of DNA damage response genes for prognostication and immunophenotype of non-G-CIMP glioblastomas

2021 ◽  
Author(s):  
Bowen Li ◽  
Fangfang Liu ◽  
Weihong Hu ◽  
Rui Li ◽  
Amandine Etcheverry ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Risk Score ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Close Correlation ◽  
Lower Grade ◽  
Mgmt Methylation ◽  
Damage Response

Abstract Background Dysregulation and dysfunction of DNA damage response (DDR) have prognostic and predictive implications for glioblastomas (GBMs) without glioma-CpGs island methylator phenotype (G-CIMP); mathematical modeling based on DNA methylation abnormality in DDR genes may serve as clinically useful biomarkers. Methods Independent cohorts of non-G-CIMP GBMs and IDH wild type (wt) lower-grade gliomas (LGGs) from local and public databases were included for discovery and validation of a multimarker signature, combined using a RISK score model. Different bioinformatic and functional experiments were performed for biological validation. Results By analyzing DNA methylation microarray data of DDR genes, we totally identified five CpGs, each of which was significantly correlated with overall survival (OS) of non-G-CIMP GBMs, independent of age, treatments and the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status. A RISK score signature of the 5 CpGs was constructed and validated to powerfully and independently prognosticate prognosis in non-G-CIMP GBMs. It also showed good discriminating value in stratified cohorts by patient age and MGMT methylation status. Bioinformatic analysis revealed a close correlation of the DDR epigenetic signature to distinct immunophenotypes of non-G-CIMP GBMs. Functional studies showed that NSUN5, epigenetically regulated by one identified CpGs, exhibited tumor-suppressor characteristics but may have immunosuppressive implications and confer TMZ resistance to GBM cells. Conclusions The epigenetic signature of DDR genes might be of promising value for refining current prognostic classification of non-G-CIMP GBMs, and its potential links to distinct immunophenotypes make it a promising biomarker candidate in the coming era of cancer immunotherapy.

Bufalin Induces Cell Death in Human Lung Cancer Cells through Disruption of DNA Damage Response Pathways

2014 ◽  
Vol 42 (03) ◽  
pp. 729-742 ◽  
Author(s):  
Shin-Hwar Wu ◽  
Tzu-Yun Wu ◽  
Yung-Ting Hsiao ◽  
Ju-Hwa Lin ◽  
Shu-Chun Hsu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Dna Methyltransferase ◽  
Human Lung Cancer ◽  
Damage Response ◽  
H460 Cells

Bufalin is a key component of a Chinese medicine (Chan Su) and has been proved effective in killing various cancer cells. Its role in inducing DNA damage and the inhibition of the DNA damage response (DDR) has been reported, but none have studied such action in lung cancer in detail. In this study, we demonstrated bufalin-induced DNA damage and condensation in NCI-H460 cells through a comet assay and DAPI staining, respectively. Western blotting indicated that bufalin suppressed the protein levels associated with DNA damage and repair, such as a DNA dependent serine/threonine protein kinase (DNA-PK), DNA repair proteins breast cancer 1, early onset (BRCA1), 14-3-3 σ (an important checkpoint keeper of DDR), mediator of DNA damage checkpoint 1 (MDC1), O6-methylguanine-DNA methyltransferase (MGMT) and p53 (tumor suppressor protein). Bufalin could activate phosphorylated p53 in NCI-H460 cells. DNA damage in NCI-H460 cells after treatment with bufalin up-regulated its ATM and ATR genes, which encode proteins functioning as sensors in DDR, and also up-regulated the gene expression (mRNA) of BRCA1 and DNA-PK. But bufalin suppressed the gene expression (mRNA) of p53 and 14-3-3 σ, however, bufalin did not significantly affect the mRNA of MGMT. In conclusion, bufalin induced DNA damage in NCI-H460 cells and also inhibited its DNA repair and checkpoint function.

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.

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

scholarly journals DNA Damage Response Genes in Osteosarcoma

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Ying Tang ◽  
Yan-xia Liu ◽  
Xiuning Huang ◽  
Peng Li
Keyword(s):  
Dna Damage ◽  
High Risk ◽  
Dna Damage Response ◽  
Risk Score ◽  
Cox Regression ◽  
Excision Repair ◽  
Gene Signature ◽  
Low Risk ◽  
Cox Regression Analysis ◽  
Damage Response

Background. Improving the osteosarcoma (OS) patients’ survival has long been a challenge, even though the disease’s treatment is on the verge of progress. DNA damage response (DDR) has traditionally been associated with carcinogenesis, tumor growth, and genomic instability. No study has used DDR genes as a signature to identify the prognosis of OS. The goal of this work was to find an effective possible DDR gene biomarker for predicting OS prognosis, which may be useful in clinical diagnosis and therapy. Methods. To assess gene methylation, univariate and multivariate cox regression analyses were performed on data from OS patients. The data were retrieved from public databases, including the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and the Gene Expression Omnibus (GEO). Results. The DDR gene signature was chosen, which included seven genes (NHEJ1, RMI2, SWI5, ERCC2, CLK2, POLG, and MLH1). In the TARGET dataset, patients were categorized into two groups: high-risk and low-risk. Patients with a high-risk score revealed a shorter OS rate (hazard ratio (HR): 3.15, 95% confidence interval (CI): 1.38–4.34, P < 0.001 ) in comparison with the patients with a low-risk score in the TARGET as a training group. The validation of the prognostic signature accuracy was carried out in relapse and validation cohorts (TARGET, n = 75; GSE21257, n = 53). The signature was found to be an independent predictive factor for OS in multivariate cox regression analysis, and a nomogram model was developed to predict an individual’s risk of OS. DDR gene signature involved in Fanconi anemia pathway, nonhomologous end−joining pathway, mismatch repair, and nucleotide excision repair pathway. Conclusions. Our study suggests that the identified novel DDR genes could be a powerful prognostic tool for prognosis evaluation and a valuable tool in predicting the risk factors in OS patients.

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.

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