The role of H3K9me2‐regulated base excision repair genes in the repair of DNA damage induced by arsenic in HaCaT cells and the effects of Ginkgo biloba extract intervention

Abstract

Arsenic is an established human carcinogen that can induce DNA damage; however, the precise mechanism remains unknown. Histone modification is of great significance in chemical toxicity and carcinogenesis. To investigate the role of histone H3K9me2 in arsenic‐induced DNA damage, HaCaT cells were exposed to sodium arsenite in this study, and the results showed that the enrichment level of H3K9me2 at the N‐methylated purine‐DNA‐glycosylase (MPG), X‐ray repair cross‐complementary gene 1 (XRCC1), and polyadenylate diphosphate ribose polymerase‐1 (PARP1) promoter regions of base‐excision repair (BER) genes was increased, which inhibited the expression of these BER genes, thereby inhibiting the repair of DNA damage and aggravating the DNA damage. Furthermore, the molecular mechanism by which H3K9me2 participates in the BER repair of arsenic‐induced DNA damage was verified based on functional loss and gain experiments. In addition, Ginkgo biloba extract can upregulate the expression of MPG, XRCC1, and PARP1 and ameliorate cell DNA damage by reducing the enrichment of H3K9me2 at repair gene promoter regions.

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

“…A role of H3K79me1 in the recruitment of 53BP1 to sites of DNA damage has been suggested, but others assigned DNA repair function to H4K20me2 [311], which can bind 53BP1 to enhance nonhomologous repair [312]. H3K9me2 abundance measured throughout the genome of HaCat cells displays a downward sodium arsenite concentration-response pattern, but using Chip-seq it increased the abundance of H3K9me2 in promoters of base excision repair genes (Mpg, Xrcc1, and Parp1), silenced their expression and aggravated DNA damage [247]. As an additional mechanism, Paul and Giri [283] hypothesize that an increase in G9a activity (the histone methyltransferase required for H3K9 dimethylation) not only increases the H3K9me2 moiety causing downregulation of tumour suppressor and DNA repair genes but also might inactivate p53 via methylation of p53 K373me2 that hinder the p53-dependent DNA repair pathway.…”

Health Effects Associated With Pre- and Perinatal Exposure to Arsenic

“…Fetal arsenic exposure can also increase the effects of skin carcinogens (topical 12-O-tetradecanoyl phorbol-13acetate, TPA) in mice by elevating the levels of CD34+ cells and expression of RAC1 (involved in self-renewal stimulation; Waalkes et al, 2008). Bronchial epithelial cells exposed to arsenic, acquired CSC-like features such as asymmetric division, • Elevated levels of H3K9me2 within promoter regions of genes involved in the Base excision repair (BER) pathway (MPG, XRCC1, and PARP1) Barchowsky et al, 1999;Smith et al, 2001;Chakraborty and De, 2009;Cooper et al, 2009;Kitchin and Conolly, 2010;Martinez et al, 2010;Smeester et al, 2011;Roy et al, 2016;Smeester and Fry, 2018;Ding et al, 2021 Interference with DNA repair • Hypomethylation in D-loop and ND6 gene along with increased expression of ND4, ND6, mtTfam, and higher mtDNA copy number Sanyal et al, 2018;Cheikhi et al, 2020 self-renewal, and increased expression of stemness genes (Chang et al, 2020;Bi et al, 2021). Arsenic-mediated malignant transformation has been linked to disruption of the KRAS gene.…”