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

Author

Listed:
  • 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
    The James Comprehensive Cancer Center)

  • Jiaquan Liu

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences)

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.

Suggested Citation

  • Xiao-Wen Yang & Xiao-Peng Han & Chong Han & James London & Richard Fishel & Jiaquan Liu, 2022. "MutS functions as a clamp loader by positioning MutL on the DNA during mismatch repair," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33479-3
    DOI: 10.1038/s41467-022-33479-3
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    References listed on IDEAS

    as
    1. Jonghyun Park & Yongmoon Jeon & Daekil In & Richard Fishel & Changill Ban & Jong-Bong Lee, 2010. "Single-Molecule Analysis Reveals the Kinetics and Physiological Relevance of MutL-ssDNA Binding," PLOS ONE, Public Library of Science, vol. 5(11), pages 1-8, November.
    2. Jiaquan Liu & Jeungphill Hanne & Brooke M. Britton & Jared Bennett & Daehyung Kim & Jong-Bong Lee & Richard Fishel, 2016. "Cascading MutS and MutL sliding clamps control DNA diffusion to activate mismatch repair," Nature, Nature, vol. 539(7630), pages 583-587, November.
    3. Jiaquan Liu & Ryanggeun Lee & Brooke M. Britton & James A. London & Keunsang Yang & Jeungphill Hanne & Jong-Bong Lee & Richard Fishel, 2019. "MutL sliding clamps coordinate exonuclease-independent Escherichia coli mismatch repair," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    4. Kyung Suk Lee & Hamza Balci & Haifeng Jia & Timothy M. Lohman & Taekjip Ha, 2013. "Direct imaging of single UvrD helicase dynamics on long single-stranded DNA," Nature Communications, Nature, vol. 4(1), pages 1-9, October.
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    Cited by:

    1. Yanan Li & Chao Liu & Xinshuo Jia & Lulu Bi & Zhiyun Ren & Yilin Zhao & Xia Zhang & Lijuan Guo & Yanling Bao & Cong Liu & Wei Li & Bo Sun, 2024. "RPA transforms RNase H1 to a bidirectional exoribonuclease for processive RNA–DNA hybrid cleavage," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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