Inhibition of nucleotide excision repair and damage response signaling by dibromoacetonitrile: A novel genotoxicity mechanism of a water disinfection byproduct
Inhibition of nucleotide excision repair and damage response signaling by dibromoacetonitrile: A novel genotoxicity mechanism of a water disinfection byproduct
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DOI：
10.1016/j.jhazmat.2021.127194
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发表时间：
2021-09-23
影响因子：
13.6
通讯作者：
Ibuki，Yuko
中科院分区：
文献类型：
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作者：
Komaki，Yukako;Ibuki，Yuko
二溴乙腈(DBAN)是一种致癌消毒副产物(DBP)，但它如何导致癌症尚不清楚。核苷酸切除修复(NER)是一种多功能的修复机制，用于移除巨大的DNA损伤以保持基因组的稳定，这一过程的损害与癌症的发展有关。在这项研究中，我们发现DBAN抑制了NER，并与其他DNA损伤反应一起探讨了其机制。用DBAN处理人角质形成细胞HaCaT，然后用紫外线(UV)作为DNA损伤的模型诱导剂，去除需要NER的嘧啶二聚体。DBAN预处理加剧了紫外线的细胞毒性，抑制了嘧啶二聚体的修复。DBAN处理延缓了NER蛋白、转录因子IIH(TFIIH)和色素性干皮病互补组G(XPG)在DNA损伤部位的募集，以及随后的缺口填充过程。此外，DBAN还抑制了紫外线诱导的双链断裂(DSB)的形成，以及广泛使用的DNA损伤标记物-组蛋白H_2AX(γ-H_2AX)的磷酸化。综上所述，DBAN可以对DNA损伤反应中的NER过程和磷酸化途径产生负面影响。本研究首次将抑制NER和损伤反应信号作为一种DBP的遗传毒性机制，为DBP的致癌作用奠定了基础。
Dibromoacetonitrile (DBAN) is a carcinogenic disinfection byproduct (DBP) but how it precipitates cancer is unknown. Nucleotide excision repair (NER) is a versatile repair mechanism for removing bulky DNA lesions to maintain genome stability, and impairment of this process is associated with cancer development. In this study, we found that DBAN inhibited NER and investigated its mechanism with other DNA damage responses. Human keratinocytes HaCaT were treated with DBAN followed by ultraviolet (UV) as a model inducer of DNA damage, pyrimidine dimers, which require NER for the removal. DBAN pretreatment exacerbated UV-cytotoxicity, and inhibited the repair of pyrimidine dimers. DBAN treatment delayed the recruitment of NER proteins, transcription factor IIH (TFIIH) and xeroderma pigmentosum complementation group G (XPG), to DNA damaged sites, and subsequent gap filling process. Moreover, DBAN suppressed the UV-induced double strand breaks (DSBs) formation, as well as phosphorylated histone H2AX (γ-H2AX), a widely used DNA damage marker. Altogether, DBAN could negatively impact the NER process and phosphorylation pathway responding to DNA damage. This study was the first to identify the inhibition of NER and damage response signaling as a genotoxicity mechanism of a class of DBPs and it may serve as a foundation for DBP carcinogenesis.