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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 ( Mlh3   DN/DN  ) harboring a mutation within this conserved domain that is predicted to generate a protein that is catalytically inert.  Mlh3   DN/DN   males, like fully null  Mlh3   -/-   males, have no spermatozoa and are infertile, yet spermatocytes have grossly normal DSBs and synapsis events in early prophase I. Unlike  Mlh3   -/-   males, mutation of the endonuclease domain within MLH3 permits normal loading and frequency of MutLγ in pachynema. However, key DSB repair factors (RAD51) and mediators of CO pathway choice (BLM helicase) persist into pachynema in  Mlh3   DN/DN   males, indicating a temporal delay in repair events and revealing a mechanism by which alternative DSB repair pathways may be selected. While  Mlh3   DN/DN   spermatocytes retain only 22% of wildtype chiasmata counts, this frequency is greater than observed in  Mlh3   -/-   males (10%), suggesting that the allele may permit partial endonuclease activity, or that other pathways can generate COs from these MutLγ-defined repair intermediates in  Mlh3   DN/DN   males. Double mutant mice homozygous for the  Mlh3   DN/DN   and  Mus81   -/-   mutations show losses in chiasmata close to those observed in  Mlh3   -/-   males, indicating that the MUS81-EME1-regulated crossover pathway can only partially account for the increased residual chiasmata in  Mlh3   DN/DN   spermatocytes. Our data demonstrate that mouse spermatocytes bearing the MLH1-MLH3 DN/DN  complex display the proper loading of factors essential for CO resolution (MutSγ, CDK2, HEI10, MutLγ). Despite these functions, mice bearing the  Mlh3   DN/DN   allele show defects in the repair of meiotic recombination intermediates and a loss of most chiasmata.

A mutation in the endonuclease domain of mouse MLH3 reveals novel roles for MutLγ during crossover formation in meiotic prophase I