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Microcystin-LR-induced nuclear translocation of cGAS promotes mutagenesis in human hepatocytes by impeding homologous recombination repair

文献类型： 外文期刊

作者： Wang, Xiaofei 1 ; Zhu, Yuchen 1 ; Lu, Wenzun 1 ; Guo, Xiaoying 3 ; Chen, Liuzeng 1 ; Zhang, Ning 1 ; Chen, Shaopeng 4 ; Ge, Chunmei 1 ; Xu, Shengmin 2 ;

作者机构： 1.Hefei Univ, Sch Biol Food & Environm, Hefei 230601, Peoples R China

2.Anhui Univ, Informat Mat & Intelligent Sensing Lab Anhui Prov, Hefei 230601, Peoples R China

3.Anhui Acad Agr Sci, Inst Agr Engn, Hefei 230031, Peoples R China

4.Wannan Med Coll, Sch Publ Hlth, Wuhu 241002, Peoples R China

关键词： Microcystin-LR (MC-LR); Human normal hepatic (HL-7702) cells; Mutagenicity; Cyclic guanosine monophosphate-adenosine; monophosphate synthase (cGAS); Homologous recombination (HR)

期刊名称：TOXICOLOGY LETTERS （ 影响因子：3.5； 五年影响因子：3.8 ）

ISSN： 0378-4274

年卷期： 2023 年 373 卷

页码：

收录情况： SCI

摘要： Microcystin-LR (MC-LR) has been recognized as a typical hepatotoxic cyclic peptides produced by cyanobacteria. Nowadays, due to the frequent occurrence of cyanobacterial blooms, the underlying hepatotoxic mechanism of MC-LR has become the focus of attention. In our present work, the mutagenic effect of MC-LR on human normal hepatic (HL-7702) cells regulated by cGAS was mainly studied. Here, we showed that exposure to MC-LR for 1-4 days could activate the cGAS-STING signaling pathway and then trigger immune response in HL-7702 cells. Notably, relative to the treatment with 1 mu M MC-LR for 1-3 days, it was observed that when HL-7702 cells were exposed to 1 mu M MC-LR for 4 days, the mutation frequency at the Hprt locus was remarkably increased. In addition, cGAS in HL-7702 cells was also found to complete the nuclear translocation after 4-day exposure. Moreover, co-immunoprecipitation and homologous recombination (HR)-directed DSB repair assay were applied to show that homologous recombination repair was inhibited after 4-day exposure. However, the intervention of the nuclear translocation of cGAS by transfecting BLK overexpression plasmid restored homologous recombination repair and reduced the mutation frequency at the Hprt locus in HL-7702 cells exposed to MC-LR. Our study unveiled the distinct roles of cGAS in the cytoplasm and nucleus of human hepatocytes as well as potential mutagenic mechanism under the early and late stage of exposure to MC-LR, and provided a novel insight into the prevention and control measures about the hazards of cGAS-targeted MC-LR.

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