{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMLH3 is an evolutionarily conserved MutL homolog that plays critical roles in both DNA mismatch repair (MMR) and meiotic recombination. In germ cells, MLH3 partners with MLH1 to localize to meiotic chromosomes at mid pachynema, ensuring proper binding and stabilization of recombination intermediates that are essential for the formation of crossovers and accurate chromosome segregation. Disruption of MLH3 function leads to a dramatic reduction in crossovers (with only 10–15% of normal events remaining) and consequent reproductive failure, as evidenced by sterility in male mice and oocyte defects in females."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its meiotic functions, MLH3 contributes to genomic stability in somatic tissues through its involvement in DNA repair processes that suppress microsatellite instability and tumorigenesis. Its genetic ablation, either alone or in combination with deficiencies in other MMR proteins like PMS2, increases gastrointestinal tumor susceptibility by compromising the repair of replication errors and promoting frameshift mutations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMLH3 also influences the adaptive immune response through its roles in class switch recombination (CSR) and somatic hypermutation (SHM). Although its deficiency can result in an increased frequency of mutations within immunoglobulin genes, these alterations underline a regulatory function that normally limits SHM accumulation and shapes the spectrum of mutations during antibody diversification."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its canonical roles, MLH3 has been implicated as a key driver of somatic repeat expansion in disease contexts such as Huntington’s disease and the Fragile X-related disorders. In these models, both MLH1 and MLH3 are essential for the CAG or microsatellite repeat expansions that correlate with pathology, with MLH3’s endonuclease activity being critical for promoting these expansion events."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdvanced single-cell analyses have contributed to the understanding of MLH3’s function by revealing its integration into broad meiotic gene-regulatory programs and its potential linkage to rare pathological processes in the gonads. Furthermore, modeling human variants in MLH3 has uncovered that hypomorphic alleles can lead to age-dependent reproductive decline and embryo loss, highlighting the protein’s importance in preventing aneuploidy and maintaining fertility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, mechanistic studies have demonstrated that the MLH1–MLH3 complex coordinates with alternative crossover pathways, such as those mediated by MUS81, to regulate crossover frequency and position during meiotic prophase I. In the absence of MLH3, other repair pathways are insufficient to fully restore crossover numbers, further affirming its primary role in directing MutLγ-mediated recombination events."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Steven M Lipkin, Peter B Moens, Victoria Wang, et al. 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