Bangor University, School of Medical Sciences, Bangor, LL57 2UW, United Kingdom.
Bangor University, Bangor Wetlands Group, School of Biological Sciences, Bangor, LL57 2UW, United Kingdom.
Sci Rep. 2017 Oct 6;7(1):12730. doi: 10.1038/s41598-017-13033-8.
Chlorination of drinking water protects humans from water-born pathogens, but it also produces low concentrations of dibromoacetonitrile (DBAN), a common disinfectant by-product found in many water supply systems. DBAN is not mutagenic but causes DNA breaks and elevates sister chromatid exchange in mammalian cells. The WHO issued guidelines for DBAN after it was linked with cancer of the liver and stomach in rodents. How this haloacetonitrile promotes malignant cell transformation is unknown. Using fission yeast as a model, we report here that DBAN delays G1-S transition. DBAN does not hinder ongoing DNA replication, but specifically blocks the serine 345 phosphorylation of the DNA damage checkpoint kinase Chk1 by Rad3 (ATR) at broken replication forks. DBAN is particularly damaging for cells with defects in the lagging-strand DNA polymerase delta. This sensitivity can be explained by the dependency of pol delta mutants on Chk1 activation for survival. We conclude that DBAN targets a process or protein that acts at the start of S phase and is required for Chk1 phosphorylation. Taken together, DBAN may precipitate cancer by perturbing S phase and by blocking the Chk1-dependent response to replication fork damage.
饮用水氯化处理可以保护人类免受水源性病原体的侵害，但也会产生低浓度的二溴乙腈（DBAN），这是许多供水系统中常见的消毒剂副产物。DBAN 没有致突变性，但会导致 DNA 断裂，并增加哺乳动物细胞中的姐妹染色单体交换。在世卫组织将 DBAN 与啮齿动物的肝和胃癌联系起来之后，发布了 DBAN 指导方针。这种卤代乙腈如何促进恶性细胞转化尚不清楚。我们使用裂殖酵母作为模型，在这里报告 DBAN 会延迟 G1-S 期过渡。DBAN 不会阻碍正在进行的 DNA 复制，但特别会阻止断裂复制叉处的 DNA 损伤检查点激酶 Chk1（ATR 激酶 Rad3）的丝氨酸 345 磷酸化。对于滞后链 DNA 聚合酶 delta 有缺陷的细胞，DBAN 特别有害。这种敏感性可以通过 pol delta 突变体对 Chk1 激活的依赖性来解释，这对生存是必需的。我们得出的结论是，DBAN 针对的是 S 期开始时起作用的过程或蛋白质，并且需要 Chk1 磷酸化。总之，DBAN 可能会通过扰乱 S 期和阻断 Chk1 依赖的复制叉损伤反应来引发癌症。
