Mechanism of Cadmium-Mediated Inhibition of Msh2-Msh6 Function in DNA Mismatch Repair

Wieland, Markus; Levin, Mikhail K.; Hingorani, Karan S.; Biro, F. Noah; Hingorani, Manju M.

Mechanism of Cadmium-Mediated Inhibition of Msh2-Msh6 Function in DNA Mismatch Repair

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Datum

2009

Autor:innen

Wieland, Markus

Levin, Mikhail K.

Hingorani, Karan S.

Biro, F. Noah

Hingorani, Manju M.

DOI (zitierfähiger Link)

https://doi.org/10.1021/bi9001248

Sammlungen

Chemie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

Biochemistry. American Chemical Society (ACS). 2009, 48(40), pp. 9492-9502. ISSN 0006-2960. eISSN 1520-4995. Available under: doi: 10.1021/bi9001248

Zusammenfassung

The observation that Cadmium (Cd²⁺) inhibits Msh2-Msh6, which is responsible for identifying base pair mismatches and other discrepancies in DNA, has led to the proposal that selective targeting of this protein and consequent suppression of DNA repair or apoptosis promote the carcinogenic effects of the heavy metal toxin. It has been suggested that Cd²⁺ binding to specific sites on Msh2-Msh6 blocks its DNA binding and ATPase activities. To investigate the mechanism of inhibition, we measured Cd²⁺ binding to Msh2-Msh6, directly and by monitoring changes in protein structure and enzymatic activity. Global fitting of the data to a multiligand binding model revealed that binding of about 100 Cd²⁺ ions per Msh2-Msh6 results in its inactivation. This finding indicates that the inhibitory effect of Cd²⁺ occurs via a nonspecific mechanism. Cd²⁺ and Msh2-Msh6 interactions involve cysteine sulfhydryl groups, and the high Cd²⁺:Msh2-Msh6 ratio implicates other ligands such as histidine, aspartate, glutamate, and the peptide backbone as well. Our study also shows that cadmium inactivates several unrelated enzymes similarly, consistent with a nonspecific mechanism of inhibition. Targeting of a variety of proteins, including Msh2-Msh6, in this generic manner would explain the marked broad-spectrum impact of Cd²⁺ on biological processes. We propose that the presence of multiple nonspecific Cd²⁺ binding sites on proteins and their propensity to change conformation on interaction with Cd²⁺ are critical determinants of the susceptibility of corresponding biological systems to cadmium toxicity.

Fachgebiet (DDC)

540 Chemie

Zitieren

ISO 690

WIELAND, Markus, Mikhail K. LEVIN, Karan S. HINGORANI, F. Noah BIRO, Manju M. HINGORANI, 2009. Mechanism of Cadmium-Mediated Inhibition of Msh2-Msh6 Function in DNA Mismatch Repair. In: Biochemistry. American Chemical Society (ACS). 2009, 48(40), pp. 9492-9502. ISSN 0006-2960. eISSN 1520-4995. Available under: doi: 10.1021/bi9001248

BibTex

@article{Wieland2009-10-13Mecha-58137,
  year={2009},
  doi={10.1021/bi9001248},
  title={Mechanism of Cadmium-Mediated Inhibition of Msh2-Msh6 Function in DNA Mismatch Repair},
  number={40},
  volume={48},
  issn={0006-2960},
  journal={Biochemistry},
  pages={9492--9502},
  author={Wieland, Markus and Levin, Mikhail K. and Hingorani, Karan S. and Biro, F. Noah and Hingorani, Manju M.}
}

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    <dcterms:abstract xml:lang="eng">The observation that Cadmium (Cd&lt;sup&gt;2+&lt;/sup&gt;) inhibits Msh2-Msh6, which is responsible for identifying base pair mismatches and other discrepancies in DNA, has led to the proposal that selective targeting of this protein and consequent suppression of DNA repair or apoptosis promote the carcinogenic effects of the heavy metal toxin. It has been suggested that Cd&lt;sup&gt;2+&lt;/sup&gt; binding to specific sites on Msh2-Msh6 blocks its DNA binding and ATPase activities. To investigate the mechanism of inhibition, we measured Cd&lt;sup&gt;2+&lt;/sup&gt; binding to Msh2-Msh6, directly and by monitoring changes in protein structure and enzymatic activity. Global fitting of the data to a multiligand binding model revealed that binding of about 100 Cd&lt;sup&gt;2+&lt;/sup&gt; ions per Msh2-Msh6 results in its inactivation. This finding indicates that the inhibitory effect of Cd&lt;sup&gt;2+&lt;/sup&gt; occurs via a nonspecific mechanism. Cd&lt;sup&gt;2+&lt;/sup&gt; and Msh2-Msh6 interactions involve cysteine sulfhydryl groups, and the high Cd&lt;sup&gt;2+&lt;/sup&gt;:Msh2-Msh6 ratio implicates other ligands such as histidine, aspartate, glutamate, and the peptide backbone as well. Our study also shows that cadmium inactivates several unrelated enzymes similarly, consistent with a nonspecific mechanism of inhibition. Targeting of a variety of proteins, including Msh2-Msh6, in this generic manner would explain the marked broad-spectrum impact of Cd&lt;sup&gt;2+&lt;/sup&gt; on biological processes. We propose that the presence of multiple nonspecific Cd&lt;sup&gt;2+&lt;/sup&gt; binding sites on proteins and their propensity to change conformation on interaction with Cd&lt;sup&gt;2+&lt;/sup&gt; are critical determinants of the susceptibility of corresponding biological systems to cadmium toxicity.</dcterms:abstract>
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