Global H3K79 di-methylation mediates DNA damage response to PAH exposure in Chinese coke oven workers
2021
Zhang, Zhengbao | Xing, Xiumei | Jiang, Shuyun | Qiu, Chunfang | Mo, Ziying | Chen, Shen | Chen, Liping | Wang, Qing | Xiao, Yongmei | Dong, Guanghui | Zheng, Yuxin | Chen, Wen | Li, Daochuan
Polycyclic aromatic hydrocarbons (PAHs) are the main contaminants of coke oven emissions which can induce serious genetic damage in coke oven workers. Epigenetic alternations play essential roles in the regulation of DNA damage effect of PAHs. Previous studies indicate that H3K79 di-methylation (H3K79me2) is integral in DNA damage repair. However, the potential role of H3K79me2 in DNA damage response (DDR) following PAHs exposure is still unclear. In this study, we recruited 256 male coke oven workers and control workers, and examined H3K79me2 and DNA damage in their peripheral blood lymphocytes (PBLCs). The results showed that global H3K79me2 of coke oven workers was 29.3% less than that of the controls (P < 0.001). The H3K79me2 was negatively correlated with the concentration of urinary 1-hydroxypyrene (1-OHP) (β = -0.235, P < 0.001) and level of genetic damage evaluated by comet assay (βTₐᵢₗ DNA % = -0.313, P < 0.001; βOTM = -0.251, P = 0.008). Consistently, we found that benzo(a)pyrene (BaP) inhibited H3K79me2 in immortalized human bronchial epithelial (HBE) cells in a time-dependent manner. In order to explore the function of H3K79me2 in PAHs DDR, we established histone 3.1/3.3 K79A mutant cells (H3K79 A) to suppress H3K79me2. H3K79 A cells showed more serious DNA damage and decreased cell viability than control cells after BaP treatment. In addition, we also found that the expression of DOT1L, the only methyltransferase in H3K79, was repressed by BaP dose-dependently. DOT1L knockdown resulted in decreased H3K79me2 level and aggravated DNA damage after BaP exposure. This suggests that BaP induces H3K79me2 repression via inhibiting DOT1L expression. In conclusion, these findings indicate that PAH exposure decreases the level of global H3K79me2, which is integral for DNA damage response regulation of PAHs.
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