Evidence That Msh1p Plays Multiple Roles in Mitochondrial Base Excision Repair

Abstract

Mitochondrial DNA is thought to be especially prone to oxidative damage by reactive oxygen species generated through electron transport during cellular respiration. This damage is mitigated primarily by the base excision repair (BER) pathway, one of the few DNA repair pathways with confirmed activity on mitochondrial DNA. Through genetic epistasis analysis of the yeast Saccharomyces cerevisiae, we examined the genetic interaction between each of the BER proteins previously shown to localize to the mitochondria. In addition, we describe a series of genetic interactions between BER components and the MutS homolog MSH1, a respiration-essential gene. We show that, in addition to their variable effects on mitochondrial function, mutant msh1 alleles conferring partial function interact genetically at different points in mitochondrial BER. In addition to this separation of function, we also found that the role of Msh1p in BER is unlikely to be involved in the avoidance of large-scale deletions and rearrangements.

The Antibiotic Monensin Causes Cell Cycle Disruption ofToxoplasma gondiiMediated through the DNA Repair Enzyme TgMSH-1

“…Most of our understanding of the function of MutS homologues is based on studies of nuclear proteins. However, mitochondrial MutS homologues, such as MSH1 from Saccharomyces cerevisiae, have been shown to function in base excision repair, protecting the mitochondria from oxidative damage (29). A role for mitochondrial MSHs in regulating the cell cycle akin to that of nuclear MSHs has not been established, but our data indicate that this could be the case in T. gondii.…”

Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations

“…The ARG8 insertion causes a rho − phenotype but reverts to rho + when the deletion occurs. Deletions between long direct repeats are not affected by mip1 mutations but are increased by din7 and msh1 mutants, which are implicated in mtDNA recombination and nucleoid assembly [47, 48]. …”

The human MSH5 (MutS Homolog 5) protein localizes to mitochondria and protects the mitochondrial genome from oxidative damage

“…The msh1 (muts homolog 1) gene encodes a mitochondrial protein that binds base-base mismatches and msh1 disruption leads to a petite phenotype with large scale rearrangements and deletions of mtDNA (Reenan and Kolodner, 1992). Several studies suggest that mismatch repair is not the primary function of Msh1p that likely functions in mitochondrial base excision repair (BER) pathway and plays an important role in the prevention of mtDNA oxidative lesions by stimulating mitochondrial recombination in yeast (Dzierzbicki et al, 2004;Kaniak et al, 2009;Mookerjee and Sia, 2006;Pogorzala et al, 2009). In plants, MSH1 functions within the mitochondrion and participates in DNA recombination surveillance (Xu et al, 2011).…”