Pericentromere-Specific Cohesin Complex Prevents Meiotic Pericentric DNA Double-Strand Breaks and Lethal Crossovers

Mol Cell. 2018 Aug 16;71(4):540-553.e4. doi: 10.1016/j.molcel.2018.06.035. Epub 2018 Aug 2.

Abstract

In most eukaryotes, meiotic crossovers are essential for error-free chromosome segregation but are specifically repressed near centromeres to prevent missegregation. Recognized for >85 years, the molecular mechanism of this repression has remained unknown. Meiotic chromosomes contain two distinct cohesin complexes: pericentric complex (for segregation) and chromosomal arm complex (for crossing over). We show that the pericentric-specific complex also actively represses pericentric meiotic double-strand break (DSB) formation and, consequently, crossovers. We uncover the mechanism by which fission yeast heterochromatin protein Swi6 (mammalian HP1-homolog) prevents recruitment of activators of meiotic DSB formation. Localizing missing activators to wild-type pericentromeres bypasses repression and generates abundant crossovers but reduces gamete viability. The molecular mechanism elucidated here likely extends to other species, including humans, where pericentric crossovers can result in disorders, such as Down syndrome. These mechanistic insights provide new clues to understand the roles played by multiple cohesin complexes, especially in human infertility and birth defects.

Keywords: DNA double-strand break; Rec11; STAG3; chromosome missegregation; cohesin; crossover; heterochromatin; infertility; meiosis; pericentric repression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Centromere / metabolism
  • Centromere / ultrastructure
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosome Segregation
  • Crossing Over, Genetic
  • DNA Breaks, Double-Stranded
  • DNA, Fungal / genetics*
  • DNA, Fungal / metabolism
  • Heterochromatin / chemistry
  • Heterochromatin / metabolism
  • Meiosis*
  • Schizosaccharomyces / genetics*
  • Schizosaccharomyces / metabolism
  • Schizosaccharomyces pombe Proteins / genetics*
  • Schizosaccharomyces pombe Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA, Fungal
  • Heterochromatin
  • Schizosaccharomyces pombe Proteins
  • Swi6 protein, S pombe
  • cohesins