The Involvement of ERCC2/XPD and ERCC6/CSB Wild Type Alleles in Protection Against Aging and Cancer

Савина, Н. В.; Никитченко, Н. В.; Kuzhir, Tatyana D.; Rolevich, A.I.; Krasny, S.; Гончарова, Р. И.

doi:10.2174/1874609810666170707101548

Cited by 6 publications

(6 citation statements)

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“…It should be investigated in the future at which extent this defect, if confirmed in all CS patients, is correlated with and participates to the severity of the disease, whether CSA is implicated in the same pathway as CSB, and also whether it is operating in UVSS patients that lack the progeroid phenotype and whose cells do not display the HTRA3/POLG1/mitochondrial defect 22 . Finally, these data provide a DNA repair-independent mechanistic explanation for the reported association between high CSB levels and tumor proliferation 55 , and CSB polymorphism association with longevity 62 , supporting a key regulatory role of CSB in the ageing/cancer axis.…”

Section: Discussionmentioning

confidence: 51%

CSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence

et al. 2019

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Cellular senescence has causative links with ageing and age-related diseases, however, it remains unclear if progeroid factors cause senescence in normal cells. Here, we show that depletion of CSB, a protein mutated in progeroid Cockayne syndrome (CS), is the earliest known trigger of p21-dependent replicative senescence. CSB depletion promotes overexpression of the HTRA3 protease resulting in mitochondrial impairments, which are causally linked to CS pathological phenotypes. The CSB promoter is downregulated by histone H3 hypoacetylation during DNA damage-response. Mechanistically, CSB binds to the p21 promoter thereby downregulating its transcription and blocking replicative senescence in a p53-independent manner. This activity of CSB is independent of its role in the repair of UV-induced DNA damage. HTRA3 accumulation and senescence are partially rescued upon reduction of oxidative/nitrosative stress. These findings establish a CSB/p21 axis that acts as a barrier to replicative senescence, and link a progeroid factor with the process of regular ageing in human.

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Section: Discussionmentioning

confidence: 51%

CSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence

et al. 2019

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“…For example, the MSH2 65 and MSH6 66 played roles in mismatch repair; The RAD51 65 played a role in homologous recombination; The SMC5 67 and DNA ligase (LIG1) 68 were with a role in chromosome structural maintenance; CHD1 69 and CHD4 70 were the critical chromatin remodelers. Some genes previously reported to be associated with genome instability, including the DNA endonuclease ERCC2 71,72 and ERCC6 73 , the cohesion protein NIPBL 72,74,75 , the DNA repair protein TRIP11 76 , and the chromatin remodeling factor SMARCA2 77 , were also recaptured by our method. We also observed that mutator genes were enriched in calcium ion transport (GO:0006816), glycerophospholipid biosynthesis progress (GO:0046474), and regulators of kinase activity (GO:0043549).…”

Section: Mutagene Recaptured Known and Identified New Mutator Genesmentioning

confidence: 97%

Mutation of mutator genes marks immunotherapy efficacy

Chen

Wang

Zhao

et al. 2022

Preprint

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Genomic instability is a hallmark of most cancers and presumably results from dysfunction of mutator genes. Yet methods to identify the complete catalogue of mutator genes in human and systematic investigations of their roles in cancer are lacking. Here we developed MutaGene to define genes associated with suppression of genomic instability and identified 1534 putative mutator genes based on the TCGA dataset. We observed that cancer patients with deficiency of mutator genes, in contrast to other genes in cancer pathways or DNA repair pathways, were coupled with strong immunogenicity, e.g., elevated neoantigen burden, immune infiltration, and expression of immune checkpoint inhibitors. The results suggest that patients with deficiency of mutator genes may be favorable candidates for immunotherapy due to their elevated mutation burden. We next integrated the mutator gene catalogue with data of cancer patients post immune checkpoint blockade treatment in the MSK-IMPACT cohort. We found that deficiency of mutator genes, particularly the ones suppressing insertion-deletion mutations, predicted strong anti-tumor effects of the immunotherapy and positive clinical outcomes. Taken together, the mutator genes identified in this study enabled fresh insights into genome instability and serve as robust biomarkers for cancer immunotherapy.

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“…Single nucleotide polymorphisms have been identified in several exons of the ERCC6 gene, such as rs2228528, rs228526, and rs2228529. The mutant of ERCC6 gene has been largely investigated in a variety of cancers [7][8][9], but the effect of ERCC polymorphism in different genetic loci and cancers is not same.…”

Section: Introductionmentioning

confidence: 99%

“…This mutation in the ERCC6 rs2228526 may diminish its activity, further resulting in a defect in overall NER pathway. Recent studies have reported the association between ERCC6 rs2228526 polymorphism and risks of various cancers [7,[10][11][12][13][14][15][16][17][18][19][20][21][22]. However, the results of these studies remained controversial.…”

Section: Introductionmentioning

confidence: 99%

Genetic Association of ERCC6 rs2228526 Polymorphism with the Risk of Cancer: Evidence from a Meta‐Analysis

Lin

et al. 2022

BioMed Research International

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At present, several studies have assessed the association between ERCC6 rs2228526 polymorphism and the risk of cancer. However, the association remained controversial. To provide a more accurate estimate on the association, we performed a meta-analysis search of case-control studies on the associations of ERCC6 rs2228526 with susceptibility to cancer. PubMed, Embase, Google Scholar, Wanfang database, and Chinese National Knowledge Infrastructure databases (CNKI) China Biological Medicine Database (CBM) (up to August 2021) were searched to identify eligible studies. The effect summary odds ratio (OR) with 95% confidence intervals (CI) was applied to assay the association between the ERCC6 rs2228526 polymorphism and the risk of cancer. 14 studies included 15 case-control studies which contained 5,856 cases, and 6,387 controls were finally determined as qualified studies for this meta-analysis. Overall, based on current studies, we found significant association between ERCC6 rs2228526 polymorphism and the risk of cancer in four genetic models [the allele model G vs. A: 1.10, (1.03–1.17); the homozygous model GG vs. AA: 1.27, (1.07–1.51); heterozygote model GA vs. AA: 1.08, (1.00–1.17); the dominant model GG + GA vs. AA: 1.10, (1.02–1.19); the recessive model GG vs. GA + AA: 1.22, (1.03–1.45)]. In the stratified analysis based on ethnicity, we found significant association in two genetic models in Asians. Further, significant genetic cancer susceptibility was found under PB control on subgroup analysis by source of control. In addition, no significant association was found in lung cancer and bladder cancer patients in subgroup analyses based on cancer style. This study suggests that the ERCC6 rs2228526 polymorphism may be associated with increased cancer risk.

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The Involvement of ERCC2/XPD and ERCC6/CSB Wild Type Alleles in Protection Against Aging and Cancer

Abstract: Homozygous wild type alleles encoding XPD and CSB proteins with optimal properties were shown to affect human lifespan, risk of developing bladder cancer, its progression and recurrence under certain conditions.

Cited by 6 publications

References 0 publications

CSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence

CSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence

Mutation of mutator genes marks immunotherapy efficacy

Genetic Association of ERCC6 rs2228526 Polymorphism with the Risk of Cancer: Evidence from a Meta‐Analysis

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