MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis

PLoS Genet. 2008 Sep 12;4(9):e1000186. doi: 10.1371/journal.pgen.1000186.


Two eukaryotic pathways for processing double-strand breaks (DSBs) as crossovers have been described, one dependent on the MutL homologs Mlh1 and Mlh3, and the other on the structure-specific endonuclease Mus81. Mammalian MUS81 has been implicated in maintenance of genomic stability in somatic cells; however, little is known about its role during meiosis. Mus81-deficient mice were originally reported as being viable and fertile, with normal meiotic progression; however, a more detailed examination of meiotic progression in Mus81-null animals and WT controls reveals significant meiotic defects in the mutants. These include smaller testis size, a depletion of mature epididymal sperm, significantly upregulated accumulation of MLH1 on chromosomes from pachytene meiocytes in an interference-independent fashion, and a subset of meiotic DSBs that fail to be repaired. Interestingly, chiasmata numbers in spermatocytes from Mus81-/- animals are normal, suggesting additional integrated mechanisms controlling the two distinct crossover pathways. This study is the first in-depth analysis of meiotic progression in Mus81-nullizygous mice, and our results implicate the MUS81 pathway as a regulator of crossover frequency and placement in mammals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Crossing Over, Genetic*
  • DNA Breaks, Double-Stranded
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Endonucleases / genetics*
  • Endonucleases / metabolism
  • Female
  • Fluorescent Antibody Technique
  • Homozygote
  • Male
  • Meiosis / genetics*
  • Mice
  • Mice, Knockout
  • MutL Protein Homolog 1
  • MutL Proteins
  • Mutation
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oocytes / cytology
  • Oocytes / metabolism
  • Sperm Count
  • Testis / cytology
  • Testis / metabolism


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • Mlh1 protein, mouse
  • Mlh3 protein, mouse
  • Nuclear Proteins
  • Endonucleases
  • Mus81 protein, mouse
  • MutL Protein Homolog 1
  • MutL Proteins