Originally published as Genetics Published Articles Ahead of Print on January 16, 2005.

Genetics, Vol. 169, 1261-1274, March 2005, Copyright © 2005
doi:10.1534/genetics.104.037515

A Novel Recombination Pathway Initiated by the Mre11/Rad50/Nbs1 Complex Eliminates Palindromes During Meiosis in Schizosaccharomyces pombe

Joseph A. Farah, Gareth Cromie, Walter W. Steiner1 and Gerald R. Smith2

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024

2 Corresponding author: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, A1-162, P.O. Box 19024, Seattle, WA 98109-1024.
E-mail: gsmith{at}fhcrc.org

DNA palindromes are rare in humans but are associated with meiosis-specific translocations. The conserved Mre11/Rad50/Nbs1 (MRN) complex is likely directly involved in processing palindromes through the homologous recombination pathway of DNA repair. Using the fission yeast Schizosaccharomyces pombe as a model system, we show that a 160-bp palindrome (M-pal) is a meiotic recombination hotspot and is preferentially eliminated by gene conversion. Importantly, this hotspot depends on the MRN complex for full activity and reveals a new pathway for generating meiotic DNA double-strand breaks (DSBs), separately from the Rec12 (ortholog of Spo11) pathway. We show that MRN-dependent DSBs are formed at or near the M-pal in vivo, and in contrast to the Rec12-dependent breaks, they appear early, during premeiotic replication. Analysis of mrn mutants indicates that the early DSBs are generated by the MRN nuclease activity, demonstrating the previously hypothesized MRN-dependent breakage of hairpins during replication. Our studies provide a genetic and physical basis for frequent translocations between palindromes in human meiosis and identify a conserved meiotic process that constantly selects against palindromes in eukaryotic genomes.




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