ArticlePLoS genetics2019
A mutation in the endonuclease domain of mouse MLH3 reveals novel roles for MutLγ during crossover formation in meiotic prophase I.
Article in PLoS genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 30 citations in OpenAlex.
- The role of DNA mismatch repair mutS/mutL homolog genes in spermatogenesis and male infertility: a systematic review and cohort study.Reproductive biology and endocrinology : RB&E · 2025Pooled it
- A mammalian-specific domain of MSH5 drives the transition from crossover licensing to designation during meiotic prophase I.bioRxiv : the preprint server for biology · 2026Article
- Distinct and overlapping roles of MutLγ, Mus81-Mms4, and STR in meiotic Holliday junction processing.Nature communications · 2026Article
- COSA-1-SLX-4 interaction directly links crossover designation with Holliday junction resolution.Science advances · 2026Article
- Maternal MLH3 dysfunction drives unexplained recurrent pregnancy loss via impaired oocyte maturation and defective decidualization.Cellular and molecular life sciences : CMLS · 2026Article
- A case of homozygous germline mutation at the MLH3 splicing site causing infertility, colon polyposis with synchronous multiple colon cancers, and osteoma.Gastroenterology report · 2026Article
- Mechanism and potential therapeutic strategies of genetic abnormalities involved in deoxyribonucleic acid double-strand breaks leading to the development of human non-obstructive azoospermia.Reproductive biology and endocrinology : RB&E · 2026Review
- SATINN v2: automated image analysis for mouse testis histology with multi-laboratory data integration†.Biology of reproduction · 2025Article
- Genetic dissection of MutL complexes in Arabidopsis meiosis.Nucleic acids research · 2025Article
- RNF212B E3 ligase is essential for crossover designation and maturation during male and female meiosis in the mouse.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Genetic dissection of crossover mutants defines discrete intermediates in mouse meiosis.Molecular cell · 2023Article
- Genetic variants underlying spermatogenic arrests in men with non-obstructive azoospermia.Cell cycle (Georgetown, Tex.) · 2023Article
- Article
- SATINN: an automated neural network-based classification of testicular sections allows for high-throughput histopathology of mouse mutants.Bioinformatics (Oxford, England) · 2022Article
- A retrotransposon insertion in MUTL-HOMOLOG 1 affects wild rice seed set and cultivated rice crossover rate.Plant physiology · 2022Article
- The Putative Endonuclease Activity of MutL Is Required for the Segmental Gene Conversion Events That Drive Antigenic Variation of the Lyme Disease Spirochete.Frontiers in microbiology · 2022Article
- Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging.Nature communications · 2021Article
- Molecular basis of the dual role of the Mlh1-Mlh3 endonuclease in MMR and in meiotic crossover formation.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Review
- Somatic CAG expansion in Huntington's disease is dependent on the MLH3 endonuclease domain, which can be excluded via splice redirection.Nucleic acids research · 2021Article
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
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/DN) 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 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 Mlh3DN/DN males, indicating a temporal delay in repair events and revealing a mechanism by which alternative DSB repair pathways may be selected. 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 permit partial endonuclease activity, or that other pathways can generate COs from these MutLγ-defined repair intermediates in Mlh3DN/DN males. Double mutant mice homozygous for the Mlh3DN/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 Mlh3DN/DN spermatocytes. Our data demonstrate that mouse spermatocytes bearing the MLH1-MLH3DN/DN complex display the proper loading of factors essential for CO resolution (MutSγ, CDK2, HEI10, MutLγ). Despite these functions, mice bearing the Mlh3DN/DN allele show defects in the repair of meiotic recombination intermediates and a loss of most chiasmata.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.