The drinking water contaminant dibromoacetonitrile delays G1-S transition and suppresses Chk1 activation at broken replication forks.
The drinking water contaminant dibromoacetonitrile delays G1-S transition and suppresses Chk1 activation at broken replication forks.
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DOI：
10.1038/s41598-017-13033-8
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发表时间：
2017-10-06
影响因子：
4.6
通讯作者：
Freeman C
中科院分区：
文献类型：
--
作者：
Caspari T;Dyer J;Fenner N;Dunn C;Freeman C
饮用水的氯化处理可以保护人类免受水传播病原体的侵害，但它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一种消毒剂副产品。DBAN不具有诱变性，但会引起DNA断裂，并提高哺乳动物细胞中姐妹染色单体的交换。在发现DBAN与啮齿动物的肝癌和胃癌有关后，世卫组织发布了DBAN的指导方针。这种卤代乙腈如何促进恶性细胞转化尚不清楚。以裂变酵母为模型，我们在这里报道DBAN延迟G1-S转变。DBAN不会阻碍正在进行的DNA复制，但会特异性地阻断DNA损伤检查点激酶Chk1在断裂复制分叉处被Rad3 （ATR）磷酸化的丝氨酸345。DBAN对存在滞后链DNA聚合酶缺陷的细胞尤其具有破坏性。这种敏感性可以通过pol δ突变体依赖Chk1激活来解释。我们得出结论，DBAN靶向作用于S期开始的一个过程或蛋白质，这是Chk1磷酸化所必需的。综上所述，DBAN可能通过扰乱S期和阻断chk1依赖的复制叉损伤反应而沉淀癌症。
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.
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