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Identification of fidelity-governing factors in human recombinases DMC1 and RAD51 from cryo-EM structures

Author

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  • Shih-Chi Luo

    (Institute of Biological Chemistry, Academia Sinica)

  • Hsin-Yi Yeh

    (Institute of Biochemical Sciences, National Taiwan University)

  • Wei-Hsuan Lan

    (National Taiwan University)

  • Yi-Min Wu

    (Institute of Biological Chemistry, Academia Sinica)

  • Cheng-Han Yang

    (Institute of Biological Chemistry, Academia Sinica)

  • Hao-Yen Chang

    (Institute of Biochemical Sciences, National Taiwan University)

  • Guan-Chin Su

    (Institute of Biochemical Sciences, National Taiwan University)

  • Chia-Yi Lee

    (Institute of Biochemical Sciences, National Taiwan University)

  • Wen-Jin Wu

    (Institute of Biological Chemistry, Academia Sinica)

  • Hung-Wen Li

    (National Taiwan University)

  • Meng-Chiao Ho

    (Institute of Biological Chemistry, Academia Sinica
    Institute of Biochemical Sciences, National Taiwan University)

  • Peter Chi

    (Institute of Biological Chemistry, Academia Sinica
    Institute of Biochemical Sciences, National Taiwan University)

  • Ming-Daw Tsai

    (Institute of Biological Chemistry, Academia Sinica
    Institute of Biochemical Sciences, National Taiwan University)

Abstract

Both high-fidelity and mismatch-tolerant recombination, catalyzed by RAD51 and DMC1 recombinases, respectively, are indispensable for genomic integrity. Here, we use cryo-EM, MD simulation and functional analysis to elucidate the structural basis for the mismatch tolerance of DMC1. Structural analysis of DMC1 presynaptic and postsynaptic complexes suggested that the lineage-specific Loop 1 Gln244 (Met243 in RAD51) may help stabilize DNA backbone, whereas Loop 2 Pro274 and Gly275 (Val273/Asp274 in RAD51) may provide an open “triplet gate” for mismatch tolerance. In support, DMC1-Q244M displayed marked increase in DNA dynamics, leading to unobservable DNA map. MD simulation showed highly dispersive mismatched DNA ensemble in RAD51 but well-converged DNA in DMC1 and RAD51-V273P/D274G. Replacing Loop 1 or Loop 2 residues in DMC1 with RAD51 counterparts enhanced DMC1 fidelity, while reciprocal mutations in RAD51 attenuated its fidelity. Our results show that three Loop 1/Loop 2 residues jointly enact contrasting fidelities of DNA recombinases.

Suggested Citation

  • Shih-Chi Luo & Hsin-Yi Yeh & Wei-Hsuan Lan & Yi-Min Wu & Cheng-Han Yang & Hao-Yen Chang & Guan-Chin Su & Chia-Yi Lee & Wen-Jin Wu & Hung-Wen Li & Meng-Chiao Ho & Peter Chi & Ming-Daw Tsai, 2021. "Identification of fidelity-governing factors in human recombinases DMC1 and RAD51 from cryo-EM structures," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20258-1
    DOI: 10.1038/s41467-020-20258-1
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    Cited by:

    1. James M. Dunce & Owen R. Davies, 2024. "BRCA2 stabilises RAD51 and DMC1 nucleoprotein filaments through a conserved interaction mode," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Shih-Chi Luo & Min-Chi Yeh & Yu-Hsiang Lien & Hsin-Yi Yeh & Huei-Lun Siao & I-Ping Tu & Peter Chi & Meng-Chiao Ho, 2023. "A RAD51–ADP double filament structure unveils the mechanism of filament dynamics in homologous recombination," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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