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The fission yeast FANCM ortholog directs non-crossover recombination during meiosis.

ABSTRACT: The formation of healthy gametes depends on programmed DNA double-strand breaks (DSBs), which are each repaired as a crossover (CO) or non-crossover (NCO) from a homologous template. Although most of these DSBs are repaired without giving COs, little is known about the genetic requirements of NCO-specific recombination. We show that Fml1, the Fanconi anemia complementation group M (FANCM)-ortholog of Schizosaccharomyces pombe, directs the formation of NCOs during meiosis in competition with the Mus81-dependent pro-CO pathway. We also define the Rad51/Dmc1-mediator Swi5-Sfr1 as a major determinant in biasing the recombination process in favor of Mus81, to ensure the appropriate amount of COs to guide meiotic chromosome segregation. The conservation of these proteins from yeast to humans suggests that this interplay may be a general feature of meiotic recombination.

SUBMITTER: Lorenz A

PROVIDER: S-EPMC3399777 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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The fission yeast FANCM ortholog directs non-crossover recombination during meiosis.

Lorenz Alexander A Osman Fekret F Sun Weili W Nandi Saikat S Steinacher Roland R Whitby Matthew C MC

Science (New York, N.Y.) 20120601 6088

The formation of healthy gametes depends on programmed DNA double-strand breaks (DSBs), which are each repaired as a crossover (CO) or non-crossover (NCO) from a homologous template. Although most of these DSBs are repaired without giving COs, little is known about the genetic requirements of NCO-specific recombination. We show that Fml1, the Fanconi anemia complementation group M (FANCM)-ortholog of Schizosaccharomyces pombe, directs the formation of NCOs during meiosis in competition with the ...[more]

PMID: 22723423

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Project description:CDKs (cyclin-dependent kinases) associate with different cyclins to form different CDK-complexes that are fundamental for an ordered cell cycle progression, and the coordination of this progression with different aspects of the cellular physiology. During meiosis programmed DNA double-strand breaks (DSBs) initiate recombination that in addition to generating genetic variability are essential for the reductional chromosome segregation during the first meiotic division, and therefore for genome stability and viability of the gametes. However, how meiotic progression and DSB formation are coordinated, and the role CDKs have in the process, is not well understood. We have used single and double cyclin deletion mutants, and chemical inhibition of global CDK activity using the cdc2-asM17 allele, to address the requirement of CDK activity for DSB formation and recombination in fission yeast. We report that several cyclins (Cig1, Cig2, and the meiosis-specific Crs1) control DSB formation and recombination, with a major contribution of Crs1. Moreover, complementation analysis indicates specificity at least for this cyclin, suggesting that different CDK complexes might act in different pathways to promote recombination. Down-regulation of CDK activity impinges on the formation of linear elements (LinEs, protein complexes required for break formation at most DSB hotspot sites). This defect correlates with a reduction in the capability of one structural component (Rec25) to bind chromatin, suggesting a molecular mechanism by which CDK controls break formation. However, reduction in DSB formation in cyclin deletion mutants does not always correspondingly correlate with a proportional reduction in meiotic recombination (crossovers), suggesting that specific CDK complexes might also control downstream events balancing repair pathways. Therefore, our work points to CDK regulation of DSB formation as a key conserved feature in the initiation of meiotic recombination, in addition to provide a view of possible roles CDK might have in other steps of the recombination process.

Project description:Accurate chromosome segregation during meiosis relies on the presence of crossover events distributed among all chromosomes. MutS? and MutL? homologs (Msh4/5 and Mlh1/3) facilitate the formation of a prominent group of meiotic crossovers that mature within the context of an elaborate chromosomal structure called the synaptonemal complex (SC). SC proteins are required for intermediate steps in the formation of MutS?-MutL? crossovers, but whether the assembled SC structure per se is required for MutS?-MutL?-dependent crossover recombination events is unknown. Here we describe an interspecies complementation experiment that reveals that the mature SC is dispensable for the formation of Mlh3-dependent crossovers in budding yeast. Zip1 forms a major structural component of the budding yeast SC, and is also required for MutS? and MutL?-dependent crossover formation. Kluyveromyces lactis ZIP1 expressed in place of Saccharomyces cerevisiae ZIP1 in S. cerevisiae cells fails to support SC assembly (synapsis) but promotes wild-type crossover levels in those nuclei that progress to form spores. While stable, full-length SC does not assemble in S. cerevisiae cells expressing K. lactis ZIP1, aggregates of K. lactis Zip1 displayed by S. cerevisiae meiotic nuclei are decorated with SC-associated proteins, and K. lactis Zip1 promotes the SUMOylation of the SC central element protein Ecm11, suggesting that K. lactis Zip1 functionally interfaces with components of the S. cerevisiae synapsis machinery. Moreover, K. lactis Zip1-mediated crossovers rely on S. cerevisiae synapsis initiation proteins Zip3, Zip4, Spo16, as well as the Mlh3 protein, as do the crossovers mediated by S. cerevisiae Zip1. Surprisingly, however, K. lactis Zip1-mediated crossovers are largely Msh4/Msh5 (MutS?)-independent. This separation-of-function version of Zip1 thus reveals that neither assembled SC nor MutS? is required for Mlh3-dependent crossover formation per se in budding yeast. Our data suggest that features of S. cerevisiae Zip1 or of the assembled SC in S. cerevisiae normally constrain MutL? to preferentially promote resolution of MutS?-associated recombination intermediates.

Dataset Information

The fission yeast FANCM ortholog directs non-crossover recombination during meiosis.

Publications

The fission yeast FANCM ortholog directs non-crossover recombination during meiosis.

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