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Published on: March 31, 2010
Human DNA polymerase α interacts with mismatch repair proteins MSH2 and MSH6
Harri M Itkonen1,2,3, Jukka Kantelinen4, Markku Vaara2
1Research group Biochemistry, Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.
Abstract:
High fidelity of genome duplication is ensured by cooperation of polymerase proofreading and mismatch repair (MMR) activities. Here, we show that human mismatch recognizing proteins MutS homolog 2 (MSH2) and MSH6 copurify and interact with replicative Pol α. This enzyme also is the replicative primase and replicates DNA with poor fidelity. We show that MSH2 associates with known human replication origins with different dynamics than DNA polymerase (Pol α). Furthermore, we explored the potential functional role of Pol α in the mismatch repair reaction using an in vitro mismatch repair assay and observed that Pol α promotes mismatch repair. Taken together, we show that human Pol α interacts with MSH2-MSH6 complex and propose that this interaction occurs during the mismatch repair reaction.
Insights
Human DNA polymerase alpha (Pol α) interacts with the MSH2-MSH6 mismatch repair complex. This interaction promotes DNA mismatch repair, enhancing genome duplication fidelity.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Genome duplication fidelity relies on DNA polymerase proofreading and mismatch repair (MMR).
- Replicative DNA polymerase alpha (Pol α) is known for its role in DNA replication and primase activity, but its fidelity is relatively poor.
Discussion:
- This study reveals a novel interaction between human DNA polymerase alpha (Pol α) and the MutS homolog 2 (MSH2)-MSH6 mismatch recognition complex.
- MSH2 exhibits distinct dynamic association with human replication origins compared to Pol α.
- Pol α's role in MMR was investigated using in vitro assays.
Key Insights:
- Human Pol α directly interacts with and copurifies with the MSH2-MSH6 MMR complex.
- Pol α was observed to promote the mismatch repair reaction in vitro.
- The findings suggest a functional interplay between Pol α and the MMR machinery during DNA replication.
Outlook:
- Further research is warranted to elucidate the precise mechanisms by which Pol α influences MMR.
- Understanding this interaction could reveal new therapeutic targets for diseases associated with MMR deficiency.
- Investigating the dynamic association of MSH2 with replication origins could shed light on MMR's temporal regulation during S-phase.
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