Msh1p counteracts oxidative lesion-induced instability of mtDNA and stimulates mitochondrial recombination in Saccharomyces cerevisiae

Kaniak, Aneta; Dzierzbicki, Piotr; Rogowska, Agata; Malc, Ewa; Fikus, Magdalena; Ciesla, Zygmunt

doi:10.1016/j.dnarep.2008.11.004

Cited by 26 publications

(24 citation statements)

References 65 publications

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“…brucei the most pronounced cell cycle effect of MSH2 loss, which is exacerbated by H 2 O 2 treatment, is the accumulation of cells with reduced amounts of kDNA (evaluated by DAPI staining) [37]. Because of these findings, and coupled with lack of a detectable kinetoplastid homologue of MSH1 (a MutS-like factor involved in mitochondrial genome repair, including oxidative damage repair) [53, 54], we hypothesized that MSH2 could provide a repair function for the trypanosomes’ mitochondrial (kDNA) genome. To test this hypothesis, we expressed T .…”

Section: Resultsmentioning

confidence: 99%

Distinct Phenotypes Caused by Mutation of MSH2 in Trypanosome Insect and Mammalian Life Cycle Forms Are Associated with Parasite Adaptation to Oxidative Stress

et al. 2015

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BackgroundDNA repair mechanisms are crucial for maintenance of the genome in all organisms, including parasites where successful infection is dependent both on genomic stability and sequence variation. MSH2 is an early acting, central component of the Mismatch Repair (MMR) pathway, which is responsible for the recognition and correction of base mismatches that occur during DNA replication and recombination. In addition, recent evidence suggests that MSH2 might also play an important, but poorly understood, role in responding to oxidative damage in both African and American trypanosomes.Methodology/Principal FindingsTo investigate the involvement of MMR in the oxidative stress response, null mutants of MSH2 were generated in Trypanosoma brucei procyclic forms and in Trypanosoma cruzi epimastigote forms. Unexpectedly, the MSH2 null mutants showed increased resistance to H2O2 exposure when compared with wild type cells, a phenotype distinct from the previously observed increased sensitivity of T. brucei bloodstream forms MSH2 mutants. Complementation studies indicated that the increased oxidative resistance of procyclic T. brucei was due to adaptation to MSH2 loss. In both parasites, loss of MSH2 was shown to result in increased tolerance to alkylation by MNNG and increased accumulation of 8-oxo-guanine in the nuclear and mitochondrial genomes, indicating impaired MMR. In T. cruzi, loss of MSH2 also increases the parasite capacity to survive within host macrophages.Conclusions/SignificanceTaken together, these results indicate MSH2 displays conserved, dual roles in MMR and in the response to oxidative stress. Loss of the latter function results in life cycle dependent differences in phenotypic outcomes in T. brucei MSH2 mutants, most likely because of the greater burden of oxidative stress in the insect stage of the parasite.

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Section: Resultsmentioning

confidence: 99%

Distinct Phenotypes Caused by Mutation of MSH2 in Trypanosome Insect and Mammalian Life Cycle Forms Are Associated with Parasite Adaptation to Oxidative Stress

et al. 2015

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“…There is so far no clear evidence for the involvement of Msh1 in mismatch repair in mitochondria, although overexpression of MSH1 appears to have an antimutator phenotype (137). Moderate overexpression of MSH1 seems to stimulate homologous recombination (138). The mechanism for this effect remains unknown.…”

Section: Msh1mentioning

confidence: 97%

Mechanism of Homologous Recombination and Implications for Aging-Related Deletions in Mitochondrial DNA

Chen

2013

Microbiol Mol Biol Rev

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SUMMARY Homologous recombination is a universal process, conserved from bacteriophage to human, which is important for the repair of double-strand DNA breaks. Recombination in mitochondrial DNA (mtDNA) was documented more than 4 decades ago, but the underlying molecular mechanism has remained elusive. Recent studies have revealed the presence of a Rad52-type recombination system of bacteriophage origin in mitochondria, which operates by a single-strand annealing mechanism independent of the canonical RecA/Rad51-type recombinases. Increasing evidence supports the notion that, like in bacteriophages, mtDNA inheritance is a coordinated interplay between recombination, repair, and replication. These findings could have profound implications for understanding the mechanism of mtDNA inheritance and the generation of mtDNA deletions in aging cells.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Bannwarth

Fragaki

et al. 2012

Mitochondrion

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Msh1p counteracts oxidative lesion-induced instability of mtDNA and stimulates mitochondrial recombination in Saccharomyces cerevisiae

Cited by 26 publications

References 65 publications

Distinct Phenotypes Caused by Mutation of MSH2 in Trypanosome Insect and Mammalian Life Cycle Forms Are Associated with Parasite Adaptation to Oxidative Stress

Distinct Phenotypes Caused by Mutation of MSH2 in Trypanosome Insect and Mammalian Life Cycle Forms Are Associated with Parasite Adaptation to Oxidative Stress

Mechanism of Homologous Recombination and Implications for Aging-Related Deletions in Mitochondrial DNA

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

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