Mechanism of cadmium-mediated inhibition of Msh2-Msh6 function in DNA mismatch repair

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

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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 Cd 2+ 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. Cd 2+ 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 Cd 2+ are critical determinants of the susceptibility of corresponding biological systems to cadmium toxicity.

Original languageEnglish (US)
Pages (from-to)9492-9502
Number of pages11
JournalBiochemistry
Volume48
Issue number40
DOIs
StatePublished - 2009

Fingerprint

DNA Mismatch Repair
Cadmium
Repair
DNA
Base Pair Mismatch
Biological Phenomena
Proteins
Protein Transport
Heavy Metals
Histidine
Aspartic Acid
DNA Repair
Cysteine
Adenosine Triphosphatases
Glutamic Acid
Biological systems
Binding Sites
Ions
Apoptosis
Ligands

ASJC Scopus subject areas

  • Biochemistry

Cite this

Wieland, M., Levin, M. K., Hingorani, K. S., Noah Biro, F., & Hingorani, M. M. (2009). Mechanism of cadmium-mediated inhibition of Msh2-Msh6 function in DNA mismatch repair. Biochemistry, 48(40), 9492-9502. https://doi.org/10.1021/bi9001248

Mechanism of cadmium-mediated inhibition of Msh2-Msh6 function in DNA mismatch repair. / Wieland, Markus; Levin, Mikhail K.; Hingorani, Karan S.; Noah Biro, F.; Hingorani, Manju M.

In: Biochemistry, Vol. 48, No. 40, 2009, p. 9492-9502.

Research output: Contribution to journalArticle

Wieland, M, Levin, MK, Hingorani, KS, Noah Biro, F & Hingorani, MM 2009, 'Mechanism of cadmium-mediated inhibition of Msh2-Msh6 function in DNA mismatch repair', Biochemistry, vol. 48, no. 40, pp. 9492-9502. https://doi.org/10.1021/bi9001248
Wieland M, Levin MK, Hingorani KS, Noah Biro F, Hingorani MM. Mechanism of cadmium-mediated inhibition of Msh2-Msh6 function in DNA mismatch repair. Biochemistry. 2009;48(40):9492-9502. https://doi.org/10.1021/bi9001248
Wieland, Markus ; Levin, Mikhail K. ; Hingorani, Karan S. ; Noah Biro, F. ; Hingorani, Manju M. / Mechanism of cadmium-mediated inhibition of Msh2-Msh6 function in DNA mismatch repair. In: Biochemistry. 2009 ; Vol. 48, No. 40. pp. 9492-9502.
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