ArticleBiochemistry2009
Mechanism of cadmium-mediated inhibition of Msh2-Msh6 function in DNA mismatch repair.
Article in Biochemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 47 citations in OpenAlex.
- Biological Effects of Human Exposure to Environmental Cadmium.Biomolecules · 2022Review
- Multifactorial Screening Reveals New Insight into Early Cadmium Exposure and Garlic Interactions in Dicentrarchus labrax.Biological trace element research · 2021Article
- Cancer DEIso: An integrative analysis platform for investigating differentially expressed gene-level and isoform-level human cancer markers.Computational and structural biotechnology journal · 2021Article
- Cell organelles as targets of mammalian cadmium toxicity.Archives of toxicology · 2020Review
- Chronic Exposure to Cadmium and Antioxidants Does Not Affect the Dynamics of Expanded CAG•CTG Trinucleotide Repeats in a Mouse Cell Culture System of Unstable DNA.Frontiers in cellular neuroscience · 2020Article
- The mutagen and carcinogen cadmium is a high-affinity inhibitor of the zinc-dependent MutLα endonuclease.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- CSE1L interaction with MSH6 promotes osteosarcoma progression and predicts poor patient survival.Scientific reports · 2017Article
- Association of MSH6 mutation with glioma susceptibility, drug resistance and progression.Molecular and clinical oncology · 2016Article
- Mechanistic insight into cadmium-induced inactivation of the Bloom protein.Scientific reports · 2016Article
- Altering Genomic Integrity: Heavy Metal Exposure Promotes Transposable Element-Mediated Damage.Biological trace element research · 2015Review
- Fibroblasts from long-lived rodent species exclude cadmium.The journals of gerontology. Series A, Biological sciences and medical sciences · 2015Article
- A PLAC8-containing protein from an endomycorrhizal fungus confers cadmium resistance to yeast cells by interacting with Mlh3p.Nucleic acids research · 2011Article
- Alternative splicing of SLC39A14 in colorectal cancer is regulated by the Wnt pathway.Molecular & cellular proteomics : MCP · 2011Article
- ITPA (inosine triphosphate pyrophosphatase): from surveillance of nucleotide pools to human disease and pharmacogenetics.Mutation researchReview
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 3 countries.
Funding
Abstract
The observation that Cadmium (Cd(2+)) 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(2+) 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 Cd(2+) ions per Msh2-Msh6 results in its inactivation. This finding indicates that the inhibitory effect of Cd(2+) occurs via a nonspecific mechanism. Cd(2+) and Msh2-Msh6 interactions involve cysteine sulfhydryl groups, and the high Cd(2+):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(2+) on biological processes. We propose that the presence of multiple nonspecific Cd(2+) 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.