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Mechanistic insight into cadmium-induced inactivation of the Bloom protein.

ABSTRACT: Cadmium is a toxic metal that inactivates DNA-repair proteins via multiple mechanisms, including zinc substitution. In this study, we investigated the effect of Cd(2+) 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 Cd(2+). Here, we show that Cd(2+) strongly inhibits both ATPase and helicase activities of BLM. Cd(2+) 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 Cd(2+) effects on other zinc-containing DNA-repair proteins, the ZBD appears to play a minor role in the Cd(2+)-mediated inhibition. While the Cd(2+)-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 Cd(2+) 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 Cd(2+) leading to accumulation of DNA double-strand breaks.

SUBMITTER: Qin W

PROVIDER: S-EPMC4872126 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Mechanistic insight into cadmium-induced inactivation of the Bloom protein.

Qin Wei W Bazeille Nicolas N Henry Etienne E Zhang Bo B Deprez Eric E Xi Xu-Guang XG

Scientific reports 20160519

Cadmium is a toxic metal that inactivates DNA-repair proteins via multiple mechanisms, including zinc substitution. In this study, we investigated the effect of Cd(2+) 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 Cd(2+). Here, we show that Cd(2+) strongly inhibits both ...[more]

PMID: 27194376

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Mechanistic insight into cadmium-induced inactivation of the Bloom protein.

Publications

Mechanistic insight into cadmium-induced inactivation of the Bloom protein.

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