SUMMARY
DNA nucleotide mismatches and lesion arise on chromosomes that are a complex assortment of protein and DNA (chromatin). The fundamental unit of chromatin is a nucleosome that contains ~146 bp DNA wrapped around an H2A, H2B, H3, and H4 histone octamer. We demonstrate that the mismatch recognition heterodimer hMSH2-hMSH6 disassembles a nucleosome. Disassembly requires a mismatch that provokes the formation of hMSH2-hMSH6 hydrolysis-independent sliding clamps, which translocate along the DNA to the nucleosome. The rate of disassembly is enhanced by actual or mimicked acetylation of histone H3 within the nucleosome entry-exit and dyad axis that occurs during replication and repair in vivo and reduces DNA-octamer affinity in vitro. Our results support a passive mechanism for chromatin remodeling where hMSH2-hMSH6 sliding clamps trap localized fluctuations in nucleosome positioning and/or wrapping that ultimately leads to disassembly, and highlights unanticipated strengths of the Molecular Switch Model for mismatch repair (MMR).
Background:The hMSH2-hMSH6 heterodimer must coordinate mismatch binding with dual site adenosine nucleotide processing. Results: An hMSH2-magnesium-ADP complex inhibits ATP hydrolysis by both the hMSH2 and hMSH6 subunits. Conclusion: hMSH2 regulates adenosine nucleotide processing by the hMSH2-hMSH6 mismatch recognition heterodimer. Significance: Understanding the molecular mechanism of hMSH2-hMSH6 function is crucial for elucidating the role of the mismatch repair pathway in human tumorigenesis.
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