Tolerance of DNA Mismatches in Dmc1 Recombinase-mediated DNA Strand Exchange

• Published in: The Journal of biological chemistry 2016-03, Vol.291 (10), p.4928-4938
• Main Authors: Borgogno, María V., Monti, Mariela R., Zhao, Weixing, Sung, Patrick, Argaraña, Carlos E., Pezza, Roberto J.
• Format: Article
• Language: English
• Subjects: Base Pair Mismatch; Base Sequence; Cell Cycle Proteins - metabolism; Dmc1; DNA and Chromosomes; DNA damage; DNA Mismatch Repair; DNA mismatches; DNA recombination; DNA strand exchange; DNA-binding protein; DNA-Binding Proteins - metabolism; heterologous DNA sequences; Homologous Recombination; Hop2-Mnd1; Humans; meiosis; Molecular Sequence Data; Nuclear Proteins - metabolism; Trans-Activators - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.704718

Recombination between homologous chromosomes is required for the faithful meiotic segregation of chromosomes and leads to the generation of genetic diversity. The conserved meiosis-specific Dmc1 recombinase catalyzes homologous recombination triggered by DNA double strand breaks through the exchange of parental DNA sequences. Although providing an efficient rate of DNA strand exchange between polymorphic alleles, Dmc1 must also guard against recombination between divergent sequences. How DNA mismatches affect Dmc1-mediated DNA strand exchange is not understood. We have used fluorescence resonance energy transfer to study the mechanism of Dmc1-mediated strand exchange between DNA oligonucleotides with different degrees of heterology. The efficiency of strand exchange is highly sensitive to the location, type, and distribution of mismatches. Mismatches near the 3′ end of the initiating DNA strand have a small effect, whereas most mismatches near the 5′ end impede strand exchange dramatically. The Hop2-Mnd1 protein complex stimulates Dmc1-catalyzed strand exchange on homologous DNA or containing a single mismatch. We observed that Dmc1 can reject divergent DNA sequences while bypassing a few mismatches in the DNA sequence. Our findings have important implications in understanding meiotic recombination. First, Dmc1 acts as an initial barrier for heterologous recombination, with the mismatch repair system providing a second level of proofreading, to ensure that ectopic sequences are not recombined. Second, Dmc1 stepping over infrequent mismatches is likely critical for allowing recombination between the polymorphic sequences of homologous chromosomes, thus contributing to gene conversion and genetic diversity.