MMS Exposure Promotes Increased MtDNA Mutagenesis in the Presence of Replication-Defective Disease-Associated DNA Polymerase γ Variants

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Thousands of mitochondrial DNA (mtDNA) per cell are necessary to maintain energy required for cellular survival in humans. Interfering with the mtDNA polymerase can result in mitochondrial diseases and mitochondrial toxicity. Therefore, it is important to explore new genetic and environmental mechanisms that alter the effectiveness and accuracy of mtDNA replication. This genetic study uses the budding yeast to demonstrate that heterozygous strains harboring disease-associated mutations in the mtDNA polymerase gene in the presence of a wild type copy of the mtDNA polymerase are associated with increased mtDNA point mutagenesis in the presence of methane methylsulfonate, a known base damaging agent. Further observations suggest that the inability of disease-associated variants to replicate mtDNA resulted in increased vulnerability to irreparable base damage that was likely to result in mutations when replicated. Also, this study showed that trace amounts of the environmental contaminant cadmium chloride impairs mtDNA replication but eliminates damage-induced mutagenesis in the remaining functional mitochondria. This interplay between disease-associated variant and wild type polymerase offers new insights on possible disease variation and implicates novel environmental consequences for compound heterozygous patients.

Vyšlo v časopise: MMS Exposure Promotes Increased MtDNA Mutagenesis in the Presence of Replication-Defective Disease-Associated DNA Polymerase γ Variants. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004748
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004748

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