title: 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.
authors.affiliation: College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qin
authors.affiliation: LBPA, CNRS UMR8113, IDA FR3242, ENS Cachan, Université Paris-Saclay, 94235 Cachan, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bazeille
authors.affiliation: LBPA, CNRS UMR8113, IDA FR3242, ENS Cachan, Université Paris-Saclay, 94235 Cachan, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Henry
authors.affiliation: College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: LBPA, CNRS UMR8113, IDA FR3242, ENS Cachan, Université Paris-Saclay, 94235 Cachan, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Deprez
authors.affiliation: College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China.|LBPA, CNRS UMR8113, IDA FR3242, ENS Cachan, Université Paris-Saclay, 94235 Cachan, France.
authors.forename: Xu-Guang
authors.initials: XG
authors.lastname: Xi
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D002104:Cadmium / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D004265:DNA Helicases / Q000037:antagonists & inhibitors; D004492:Edetic Acid / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D011485:Protein Binding; D053484:RecQ Helicases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D002104:Cadmium; D004247:DNA; D004492:Edetic Acid; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases