Watson-Crick base pairing is the foundation for high-fidelity DNA synthesis, repair, and recombination. However, not all of these processes occur at high-fidelity in various cellular functions. The structural basis of DNA polymerases with contrasting fidelity has been investigated extensively as reviewed recently (1). Both high-fidelity and mismatch-tolerant DNA recombination, catalyzed by RAD51 and DMC1 recombinases, respectively, are indispensable for maintaining genomic integrity and generating genetic diversity. However, it remains unknown how DMC1 overcomes the Watson-Crick forces to allow for mismatched base pairing. In a recent study (2), we used cryo-EM, MD simulations, and functional assays to suggest that the recombination fidelity is governed primarily by two structural factors involving lineage-specific residues in coordination with conserved residues: flexibility of the boundary gate to the base-pair triplet, and strength of support for the DNA backbone by a structural wall. Tight gate and weak wall render high fidelity for RAD51 because mismatched base-pairs could not fit and thus destabilize the DNA backbone, whereas loose gate and strong wall confer mismatch tolerance due to the opposite effects.
(1) How DNA polymerases catalyze replication and repair with contrasting fidelity. Wen-Jin Wu, Wei Yang, and Ming-Daw Tsai, Nature Reviews Chemistry 1, 0068 (2017). doi:10.1038/s41570-017-0068
(2) 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, Nat Commun 12, 115 (2021). doi:10.1038/s41467-020-20258-1