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- W4319294018 endingPage "1765" @default.
- W4319294018 startingPage "1750" @default.
- W4319294018 abstract "Abstract Many replicative DNA polymerases couple DNA replication and unwinding activities to perform strand displacement DNA synthesis, a critical ability for DNA metabolism. Strand displacement is tightly regulated by partner proteins, such as single-stranded DNA (ssDNA) binding proteins (SSBs) by a poorly understood mechanism. Here, we use single-molecule optical tweezers and biochemical assays to elucidate the molecular mechanism of strand displacement DNA synthesis by the human mitochondrial DNA polymerase, Polγ, and its modulation by cognate and noncognate SSBs. We show that Polγ exhibits a robust DNA unwinding mechanism, which entails lowering the energy barrier for unwinding of the first base pair of the DNA fork junction, by ∼55%. However, the polymerase cannot prevent the reannealing of the parental strands efficiently, which limits by ∼30-fold its strand displacement activity. We demonstrate that SSBs stimulate the Polγ strand displacement activity through several mechanisms. SSB binding energy to ssDNA additionally increases the destabilization energy at the DNA junction, by ∼25%. Furthermore, SSB interactions with the displaced ssDNA reduce the DNA fork reannealing pressure on Polγ, in turn promoting the productive polymerization state by ∼3-fold. These stimulatory effects are enhanced by species-specific functional interactions and have significant implications in the replication of the human mitochondrial DNA." @default.
- W4319294018 created "2023-02-07" @default.
- W4319294018 creator A5012453668 @default.
- W4319294018 creator A5012658836 @default.
- W4319294018 creator A5026723001 @default.
- W4319294018 creator A5027561485 @default.
- W4319294018 creator A5031214916 @default.
- W4319294018 creator A5053811997 @default.
- W4319294018 creator A5055244397 @default.
- W4319294018 creator A5075116498 @default.
- W4319294018 date "2023-02-06" @default.
- W4319294018 modified "2023-10-15" @default.
- W4319294018 title "Mechanism of strand displacement DNA synthesis by the coordinated activities of human mitochondrial DNA polymerase and SSB" @default.
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- W4319294018 doi "https://doi.org/10.1093/nar/gkad037" @default.