Inhibition of the Smc5/6 complex during meiosis perturbs joint molecule formation and resolution without significantly changing crossover or non-crossover levels

PLoS Genet. 2013 Nov;9(11):e1003898. doi: 10.1371/journal.pgen.1003898. Epub 2013 Nov 7.

Abstract

Meiosis is a specialized cell division used by diploid organisms to form haploid gametes for sexual reproduction. Central to this reductive division is repair of endogenous DNA double-strand breaks (DSBs) induced by the meiosis-specific enzyme Spo11. These DSBs are repaired in a process called homologous recombination using the sister chromatid or the homologous chromosome as a repair template, with the homolog being the preferred substrate during meiosis. Specific products of inter-homolog recombination, called crossovers, are essential for proper homolog segregation at the first meiotic nuclear division in budding yeast and mice. This study identifies an essential role for the conserved Structural Maintenance of Chromosomes (SMC) 5/6 protein complex during meiotic recombination in budding yeast. Meiosis-specific smc5/6 mutants experience a block in DNA segregation without hindering meiotic progression. Establishment and removal of meiotic sister chromatid cohesin are independent of functional Smc6 protein. smc6 mutants also have normal levels of DSB formation and repair. Eliminating DSBs rescues the segregation block in smc5/6 mutants, suggesting that the complex has a function during meiotic recombination. Accordingly, smc6 mutants accumulate high levels of recombination intermediates in the form of joint molecules. Many of these joint molecules are formed between sister chromatids, which is not normally observed in wild-type cells. The normal formation of crossovers in smc6 mutants supports the notion that mainly inter-sister joint molecule resolution is impaired. In addition, return-to-function studies indicate that the Smc5/6 complex performs its most important functions during joint molecule resolution without influencing crossover formation. These results suggest that the Smc5/6 complex aids primarily in the resolution of joint molecules formed outside of canonical inter-homolog pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Chromatids / genetics
  • Chromosome Segregation / genetics
  • DNA Breaks, Double-Stranded
  • DNA Repair / genetics
  • Endodeoxyribonucleases / genetics*
  • Endodeoxyribonucleases / metabolism
  • Meiosis / genetics*
  • Mice
  • Mitosis / genetics
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Recombination, Genetic
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sister Chromatid Exchange

Substances

  • Cell Cycle Proteins
  • Multiprotein Complexes
  • SMC5 protein, S cerevisiae
  • SMC6 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Endodeoxyribonucleases
  • meiotic recombination protein SPO11

Grants and funding

IL is supported by Karolinska Institutet, TK is supported by the Swedish Cancer Society, CS is supported by the Knut and Alice Wallenberg Foundation, European Research Council, Swedish Cancer Society, Cornell's and Karolinska Institute's research foundations, Vinnova, Swedish foundation for Strategic research (SSF) and the Swedish Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.