MutS functions as a clamp loader by positioning MutL on the DNA during mismatch repair

Xiao-Wen Yang, Xiao-Peng Han, Chong Han, James London, Richard Fishel () and Jiaquan Liu ()
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Xiao-Wen Yang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xiao-Peng Han: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Chong Han: University of Chinese Academy of Sciences, Chinese Academy of Sciences
James London: The Ohio State University Wexner Medical Center
Richard Fishel: The Ohio State University Wexner Medical Center
Jiaquan Liu: University of Chinese Academy of Sciences, Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Highly conserved MutS and MutL homologs operate as protein dimers in mismatch repair (MMR). MutS recognizes mismatched nucleotides forming ATP-bound sliding clamps, which subsequently load MutL sliding clamps that coordinate MMR excision. Several MMR models envision static MutS-MutL complexes bound to mismatched DNA via a positively charged cleft (PCC) located on the MutL N-terminal domains (NTD). We show MutL-DNA binding is undetectable in physiological conditions. Instead, MutS sliding clamps exploit the PCC to position a MutL NTD on the DNA backbone, likely enabling diffusion-mediated wrapping of the remaining MutL domains around the DNA. The resulting MutL sliding clamp enhances MutH endonuclease and UvrD helicase activities on the DNA, which also engage the PCC during strand-specific incision/excision. These MutS clamp-loader progressions are significantly different from the replication clamp-loaders that attach the polymerase processivity factors β-clamp/PCNA to DNA, highlighting the breadth of mechanisms for stably linking crucial genome maintenance proteins onto DNA.

Date: 2022
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DOI: 10.1038/s41467-022-33479-3

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