Rad51, Rad54, and ZMM proteins antagonize the mismatch repair system to promote fertility of budding yeast intraspecies hybrid zygotes.

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. 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.