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

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 () and Ming-Daw Tsai ()
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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
Peter Chi: Institute of Biological Chemistry, Academia Sinica
Ming-Daw Tsai: Institute of Biological Chemistry, Academia Sinica

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20258-1

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