Novel DNA mismatch-repair activity involving YB-1 in human mitochondria.
Maintenance of the mitochondrial genome (mtDNA) is essential for proper cellular function. The accumulation of damage and mutations in the mtDNA leads to diseases, cancer, and aging. Mammalian mitochondria have proficient base excision repair, but the existence of other DNA repair pathways is still unclear. Deficiencies in DNA mismatch repair (MMR), which corrects base mismatches and small loops, are associated with DNA microsatellite instability, accumulation of mutations, and cancer. MMR proteins have been identified in yeast and coral mitochondria; however, MMR proteins and function have not yet been detected in human mitochondria. Here we show that human mitochondria have a robust mismatch-repair activity, which is distinct from nuclear MMR. Key nuclear MMR factors were not detected in mitochondria, and similar mismatch-binding activity was observed in mitochondrial extracts from cells lacking MSH2, suggesting distinctive pathways for nuclear and mitochondrial MMR. We identified the repair factor YB-1 as a key candidate for a mitochondrial mismatch-binding protein. This protein localizes to mitochondria in human cells, and contributes significantly to the mismatch-binding and mismatch-repair activity detected in HeLa mitochondrial extracts, which are significantly decreased when the intracellular levels of YB-1 are diminished. Moreover, YB-1 depletion in cells increases mitochondrial DNA mutagenesis. Our results show that human mitochondria contain a functional MMR repair pathway in which YB-1 participates, likely in the mismatch-binding and recognition steps.
de Souza-Pinto
Nadja C
NC
Laboratory of Molecular Gerontology, National Institute on Aging/Intramural Research Program (NIA-IRP), National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Mason
Penelope A
PA
Hashiguchi
Kazunari
K
Weissman
Lior
L
Tian
Jingyan
J
Guay
David
D
Lebel
Michel
M
Stevnsner
Tinna V
TV
Rasmussen
Lene Juel
LJ
Bohr
Vilhelm A
VA
D002467:Cell Nucleus / Q000378:metabolism; D002702:Chloramphenicol Resistance; D053843:DNA Mismatch Repair; D004272:DNA, Mitochondrial / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption; D013347:Subcellular Fractions; D051840:Y-Box-Binding Protein 1
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human