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Novel DNA mismatch-repair activity involving YB-1 in human mitochondria
Nadja C de Souza-Pinto1, Penelope A Mason, Kazunari Hashiguchi
1Laboratory of Molecular Gerontology, National Institute on Aging/Intramural Research Program (NIA-IRP), National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Abstract:
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.
Insights
Human mitochondria possess a distinct DNA mismatch repair (MMR) pathway, separate from the nucleus. The protein YB-1 is identified as a key player in this mitochondrial MMR activity, crucial for preventing DNA mutations.
Area of Science:
- Cellular Biology
- Molecular Biology
- Genetics
Background:
- Mitochondrial genome (mtDNA) maintenance is vital for cellular function; mtDNA damage and mutations are linked to diseases, cancer, and aging.
- While base excision repair is known in mammalian mitochondria, other DNA repair pathways, like mismatch repair (MMR), remain unclear.
- MMR is crucial for correcting DNA base mismatches and small loops, preventing mutations and instability, but its presence in human mitochondria was unconfirmed.
Purpose of the Study:
- To investigate the existence and characteristics of a mismatch repair (MMR) pathway within human mitochondria.
- To identify potential protein factors involved in mitochondrial MMR distinct from nuclear MMR pathways.
- To determine the role of identified factors in mitochondrial DNA repair and mutagenesis.
Main Methods:
- Analysis of mitochondrial extracts for mismatch-binding and repair activity.
- Comparison of mitochondrial MMR activity with nuclear MMR factors (e.g., MSH2).
- Identification and characterization of potential mitochondrial MMR proteins, including YB-1 localization and functional assays.
- Assessment of mtDNA mutagenesis following YB-1 depletion.
Main Results:
- Human mitochondria exhibit robust mismatch-repair activity distinct from nuclear MMR.
- Key nuclear MMR factors were not detected in mitochondria, indicating a separate pathway.
- The protein YB-1 was identified as a mitochondrial mismatch-binding protein contributing significantly to MMR activity.
- YB-1 depletion led to decreased mitochondrial MMR activity and increased mitochondrial DNA mutagenesis.
Conclusions:
- Human mitochondria possess a functional DNA mismatch repair (MMR) pathway.
- This mitochondrial MMR pathway is distinct from the nuclear MMR system.
- The protein YB-1 plays a significant role in mitochondrial MMR, likely in mismatch binding and recognition, and its deficiency increases mtDNA mutagenesis.
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