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Rad51 and meiosis-specific Dmc1 catalyze homologous recombination (HR) between maternal and paternal chromosomes during meiosis in many sexual eukaryotes, generating three interhomolog (IH) recombination products: non-crossovers (NCOs), class I interference-sensitive crossovers (COs), and class II non-interfering COs. CO interference suppresses relatively close CO formation. Some COs form chiasmata, which physically connect homologous chromosomes and ensure proper chromosome segregation during meiosis I. Meiosis is highly relevant to speciation, with the mismatch repair (MMR) system believed to prevent IH recombination, leading to post-zygotic isolation between closely related species. We report that several Saccharomyces cerevisiae homologous recombination proteins exhibit anti-MMR activities, including Rad51, Rad54, Rad59, and synapsis-promoting ZMM proteins (Mer3, Zip1, Zip4, and Msh4) in SK1/S288c hybrid meiosis. Synapsis is a mechanism unique to meiosis in which the synaptonemal complex (SC), a zipper-like network of proteins, form between maternal and paternal chromosomes (two pairs of sister chromatids) during meiotic prophase. Srs2 (an ortholog of Escherichia coli helicase UvrD) facilitates MMR by dissembling Rad51–single-stranded DNA pre-synaptic filaments. Rad51 antagonizes MMR and Srs2. Rad54’s anti-MMR activity acts after Srs2 and outcompetes its pro-HR function to promote Rad51-mediated IH-HR in hybrid meiosis. Dmc1 and Rad51 then recruit pro-crossover ZMM proteins to promote class I IH-CO formation while limiting MMR to promote NCO formation by Sgs1 (an ortholog of E. coli RecQ helicase) and prevent class II IH-CO formation by the Mms4–Mus81 endonuclease.

This study was published in the journal “Nucleic Acids Research” on September 3, 2025. It was funded by an intramural grant of the Institute of Molecular Biology (IMB), Academia Sinica, and by research grants from Academia Sinica (AS-GCS-114-L05 to TFW) and the National Science and Technology Council (NSTC-114-2311-B-001-006-MY3 to TFW). Dr. Ting-Fang Wang (IMB, Academia Sinica) led this research project in collaboration with Dr. Yi-Ping Hsueh (IMB, Academia Sinica) and Dr. Ruey-Shyang Chen (National Chia-Yi University). Ya-Ling Hung and Chi-Ning Chuang are co-first authors.