DNA mismatch repair protein Mlh1 is required for tetravalent chromium intermediate-induced DNA damage.
DNA mismatch repair protein Mlh1 is required for tetravalent chromium intermediate-induced DNA damage.
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DOI：
10.18632/oncotarget.20150
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发表时间：
2017-10-13
期刊：
影响因子：
--
通讯作者：
Xu B
中科院分区：
文献类型：
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作者：
Wakeman TP;Yang A;Dalal NS;Boohaker RJ;Zeng Q;Ding Q;Xu B
六价铬（Cr[VI]）与职业性肺癌有关，并构成重大的公共卫生问题。当暴露于Cr[VI]时，细胞迅速内化该化合物并将其代谢为Cr[III]。Cr[VI]代谢的副产物包括不稳定的Cr[V]和Cr[IV]中间体，这些中间体被认为是Cr[VI]暴露引起的遗传毒性和致癌性的直接原因;然而，Cr中间体的致癌潜力和Cr诱导的致癌机制仍有待进一步确定。利用合成的Cr[IV]和Cr[V]化合物，我们在这里证明，Cr[IV]或Cr[V]暴露诱导DNA双链断裂;然而，这两种化合物中，哺乳动物细胞仅对Cr[V]诱导的DNA损伤有反应。暴露于Cr[V]而不是Cr[IV]，导致细胞周期检查点的启动并激活ATM激酶，ATM激酶是DNA损伤反应的关键调节因子。此外，与暴露于Cr[V]的细胞相比，暴露于Cr[IV]的细胞HPRT基因突变频率显著增加，表明Cr[IV]具有比Cr[V]更高的致突变潜力。我们还发现，MLH 1，一个关键的错配修复（MMR）蛋白，需要激活的G2/M细胞周期检查点在响应铬[VI]曝光和限制铬诱导的诱变。我们的研究结果为Cr[IV]作为Cr[VI]代谢过程中产生的最终致突变中间体提供了证据，并表明功能性MMR在铬暴露的细胞反应中至关重要。
Hexavalent chromium (Cr[VI]) is associated with occupational lung cancer and poses a significant public health concern. When exposed to Cr[VI], cells rapidly internalize this compound and metabolize it to Cr[III]. Byproducts of Cr[VI] metabolism include unstable Cr[V] and Cr[IV] intermediates that are believed to be directly responsible for the genotoxicity and carcinogenicity caused by Cr[VI] exposure; however, the carcinogenic potential of the Cr intermediates and the mechanisms of Cr-induced carcinogenesis remain to be further defined. Utilizing synthetic Cr[IV] and Cr[V] compounds, we demonstrate here that Cr[IV] or Cr[V] exposure induces DNA double-strand breaks; however, of the two compounds, mammalian cells only respond to Cr[V]-induced DNA damage. Exposure to Cr[V], but not Cr[IV], results in initiation of cell cycle checkpoints and activates the ATM kinase, a critical regulator of the DNA damage response. Furthermore, cells exposed to Cr[IV] have significantly increased mutation frequencies in the HPRT gene compared to cells exposed to Cr[V], indicating that Cr[IV] possesses a higher mutagenic potential than Cr[V]. We also find that MLH1, a critical mismatch repair (MMR) protein, is required for activation of the G2/M cell cycle checkpoint in response to Cr[VI] exposure and to limit Cr-induced mutagenesis. Our results provide evidence for Cr[IV] as the ultimate mutagenic intermediate produced during Cr[VI] metabolism and indicate that functional MMR is crucial in the cellular response to chromium exposure.