DOI: 10.1101/517748Jan 11, 2019Paper

Mutation Of MLH3 Endonuclease Motif Reveals Integration Between Crossover Pathways In Mammalian Meiosis

BioRxiv : the Preprint Server for Biology
Melissa ToledoPaula E Cohen


During meiotic prophase I, double strand breaks (DSBs) initiate homologous recombination leading to non-crossovers (NCOs) and crossovers (COs). In mouse, 10% of DSBs are designated to become COs, primarily through a pathway dependent on the MLH1-MLH3 heterodimer (MutLγ). Mlh3 contains an endonuclease domain that is critical for resolving COs in yeast. We generated a mouse Mlh3DN allele harboring a mutation within this conserved domain that is predicted to generate a protein that is catalytically inert. Mlh3DN/DN males, like fully null Mlh3-/- males, have no spermatozoa and are infertile, yet spermatocytes have normal DSBs and undergo normal synapsis events in early prophase I. Unlike Mlh3-/- males, however, mutation of the endonuclease domain within MLH3 permits normal loading and frequency of MutLγ in pachynema. However, DSB repair and CO designation factors persist in Mlh3DN/DN males, indicating a temporal delay in repair events. While Mlh3DN/DN spermatocytes retain only 22% of wildtype chiasmata counts, this frequency is greater than observed in Mlh3-/- males (10%), suggesting that the allele may be partially functional or that other pathways can generate COs from these MutLγ-defined repair intermediates in Mlh3DN/DN males, ...Continue Reading

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