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Cadmium is a mutagen that acts by inhibiting mismatch repair
Yong Hwan Jin1, Alan B Clark, Robbert J C Slebos
1Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Abstract:
Most errors that arise during DNA replication can be corrected by DNA polymerase proofreading or by post-replication mismatch repair (MMR). Inactivation of both mutation-avoidance systems results in extremely high mutability that can lead to error catastrophe. High mutability and the likelihood of cancer can be caused by mutations and epigenetic changes that reduce MMR. Hypermutability can also be caused by external factors that directly inhibit MMR. Identifying such factors has important implications for understanding the role of the environment in genome stability. We found that chronic exposure of yeast to environmentally relevant concentrations of cadmium, a known human carcinogen, can result in extreme hypermutability. The mutation specificity along with responses in proofreading-deficient and MMR-deficient mutants indicate that cadmium reduces the capacity for MMR of small misalignments and base-base mismatches. In extracts of human cells, cadmium inhibited at least one step leading to mismatch removal. Together, our data show that a high level of genetic instability can result from environmental impediment of a mutation-avoidance system.
Insights
Environmental cadmium exposure causes extreme DNA hypermutability by inhibiting mismatch repair (MMR), a critical system for genome stability. This finding highlights how environmental factors can impede DNA repair mechanisms, potentially increasing cancer risk.
Area of Science:
- Molecular Biology
- Environmental Toxicology
- Genetics
Background:
- DNA replication errors are typically corrected by DNA polymerase proofreading and mismatch repair (MMR).
- Inactivation of these systems leads to high mutability, increasing cancer risk.
- Environmental factors can also inhibit MMR, impacting genome stability.
Purpose of the Study:
- To investigate the effect of environmental cadmium exposure on DNA repair mechanisms.
- To determine if cadmium can induce hypermutability by interfering with MMR.
- To understand the implications of environmental impediments on genome stability.
Main Methods:
- Chronic exposure of yeast to cadmium.
- Analysis of mutation specificity in wild-type and MMR-deficient yeast strains.
- Inhibition assays using extracts from human cells.
Main Results:
- Cadmium exposure induced extreme hypermutability in yeast.
- Cadmium was found to reduce the MMR capacity for base-base mismatches and small misalignments.
- Cadmium inhibited a step in the mismatch removal process in human cell extracts.
Conclusions:
- Environmental cadmium exposure impedes DNA mismatch repair, leading to significant genetic instability.
- Cadmium's ability to inhibit MMR highlights the role of environmental factors in genome destabilization.
- This research underscores the link between environmental toxicants and increased cancer risk through DNA repair interference.