Abstract
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.
Highlights
Meiosis is a tightly regulated and essential process that results in the generation of gametes containing the correct haploid chromosome complement
We report subtle, yet significant, defects in meiotic progression in male and female Mus81 mice, coupled with intriguing results showing that MUS81 protein is essential for crossover control in mammals
MUS81 appears to be required for correct localization of MLH1–MLH3 complexes to paired homologous chromosomes, not for the maintenance of physical crossovers, visualized as chiasmata
Summary
Meiosis is a tightly regulated and essential process that results in the generation of gametes containing the correct haploid chromosome complement. The defining events of meiosis occur during prophase I, including the pairing of and physical association between, homologous chromosomes (synapsis), accompanied by exchange of genetic information (recombination) between these chromosome pairs. These meiotic regulatory processes are highly conserved from yeast through to humans. The process of DSB repair in mammals appears to utilize pathways similar to that seen in lower eukaryotes, such as S. cerevisiae [3,4], and results in either crossover (CO), which involves exchange of flanking DNA markers between the homologs, or non-crossover (NCO), in which the flanking DNA remains unchanged [3]. COs are physically manifested as chiasmata, which tether homologous chromosomes together to ensure correct segregation at the first meiotic division
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