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

By Farah, Joseph A.; Cromie, Gareth et al. | Genetics, April 2005 | Go to article overview

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


Farah, Joseph A., Cromie, Gareth, Steiner, Walter W., Smith, Gerald R., Genetics


ABSTRACT

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-pa1) 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-pa1 in vivo, and in contrast to the Rec12-dependent breaks, they appear early, during premeiotic replication. Analysis of mm 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.

MEIOSIS, the hallmark of sexual reproduction, allows eukaryotes to transmit through their germline all the genetic characteristics of the species to the next generation. In most species, meiosis is characterized by a high level of homologous recombination during prophase of the first meiotic division. Meiotic recombination creates new combinations of alleles, thereby increasing genetic diversity, and also generates the connection between homologs that allows their proper alignment and segregation by the meiotic spindle. Cells undergoing the meiotic program must therefore allow genome-wide recombination yet at the same time keep this recombination under control to avoid deleterious outcomes such as ectopic recombination and translocations. Cells have solved this problem by allowing recombination to happen in a timely and spatially defined manner after premeiotic DNA replication, when the recombining homologs are closely juxtaposed or synapsed (ROEDER 1997).

Recombination is stimulated by lesions in DNA. Accidental DNA lesions can be introduced into the genome from exogenous sources, such as exposure to UV and ionizing radiation or radiomimetic chemicals, or from endogenous sources, such as free radicals generated during normal cellular metabolism. These lesions threaten genome integrity but can be repaired with efficiencies that depend on the stage of the cell cycle during which they happen (LEE et al. 1997). Much more dangerous to cells are genomic DNA elements that can adopt secondary structures and be cleaved by nucleases. Such elements can be faithfully repaired by recombination with a sister or a homolog. But they can also be hotspots of DNA breakage with a high potential to recombine with ectopic sequences and thereby generate translocations. This may be one reason why DNA palindromes are underrepresented in genomes, including that of humans (LOBACHEV et al. 2000).

Cells have protein complexes to deal with such deleterious DNA elements. The best studied of these complexes is the Mrell/Rad50/Nbsl (MRN) complex (in Saccharomyces cerevisiaeXrsZ replaces Nbsl and the complex is denoted MRX). This complex is conserved from bacteriophages to mammals and is involved in many aspects of DNA metabolism (HABER 1998). The MRN complex associates with S-phase chromatin and is required for the intra-S-phase checkpoint (D'AMOURS and JACKSON 2001; MASER et al 2001; CHAHWAN et al 2003). Xenopus extracts depleted of Mre11 accumulate double-strand breaks (DSBs) during DNA replication (COSTANZO et al. 2001). This accumulation of DSBs may be the basis of MRN being essential in vertebrates (Luo et al. 1999; ZHU et al. 2001).

The involvement of the MRN complex in palindrome elimination is revealed by both in vitro and in vivo studies. …

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