Mechanistic insight into cadmium-induced inactivation of the Bloom protein.
Mechanistic insight into cadmium-induced inactivation of the Bloom protein.
复制标题
镉诱导布卢姆蛋白失活的机制研究
DOI：
10.1038/srep26225
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发表时间：
2016-05-19
影响因子：
4.6
通讯作者：
Xi XG
中科院分区：
文献类型：
--
作者：
Qin W;Bazeille N;Henry E;Zhang B;Deprez E;Xi XG
Cadmium is a toxic metal that inactivates DNA-repair proteins via multiple mechanisms, including zinc substitution. In this study, we investigated the effect of Cd2+on the Bloom protein (BLM), a DNA-repair helicase carrying a zinc-binding domain (ZBD) and playing a critical role to ensure genomic stability. One characteristics of BLM-deficient cells is the elevated rate of sister chromatid exchanges, a phenomenon that is also induced by Cd2+. Here, we show that Cd2+strongly inhibits both ATPase and helicase activities of BLM. Cd2+primarily prevents BLM-DNA interaction via its binding to sulfhydryl groups of solvent-exposed cysteine residues and, concomitantly, promotes the formation of large BLM multimers/aggregates. In contrast to previously described Cd2+effects on other zinc-containing DNA-repair proteins, the ZBD appears to play a minor role in the Cd2+-mediated inhibition. While the Cd2+-dependent formation of inactive multimers and the defect of DNA-binding were fully reversible upon addition of EDTA, the inhibition of the DNA unwinding activity was not counteracted by EDTA, indicating another mechanism of inhibition by Cd2+relative to the targeting of a catalytic residue. Altogether, our results provide new clues for understanding the mechanism behind the ZBD-independent inactivation of BLM by Cd2+leading to accumulation of DNA double-strand breaks.
