{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman MSH4 is a meiosis‐specific member of the MutS homolog family that forms a heterodimer with MSH5 to facilitate homologous recombination. The MSH4–MSH5 complex binds to DNA recombination intermediates—such as Holliday junctions—and, upon ATP binding and exchange, forms sliding clamps that help stabilize parental chromosome pairing and channel repair of programmed double‐strand breaks. These mechanistic insights underline the complex’s role in ensuring accurate chromosomal repair during meiosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations and sequence variants in MSH4 have been increasingly linked to reproductive pathologies. Several studies have reported that deleterious mutations in conserved regions of MSH4—often impairing ATP binding or disrupting its association with MSH5—are associated with premature ovarian failure, primary ovarian insufficiency, and diminished ovarian reserve in females, as well as with non‐obstructive azoospermia and other forms of primary gonadal failure in males. In diverse patient cohorts and familial studies, whole-exome sequencing has revealed pathogenic MSH4 variants that likely disrupt meiotic double-strand break repair, thereby compromising genome stability during gametogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in orchestrating homologous recombination, MSH4 function is modulated by complex regulatory mechanisms. Its interaction with MSH5 not only is critical for loading onto DNA substrates but also governs its subcellular trafficking via active nuclear export mediated by CRM1. Moreover, MSH4 is subject to post-translational modifications – such as acetylation in response to DNA damage—and alternative splicing events, which together fine-tune its activity and interactions with other components of the DNA repair machinery. These regulatory layers highlight the multifaceted control of MSH4 function in both germ cells and possibly in somatic contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Timothy Snowden, Kang-Sup Shim, Christoph Schmutte, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Formation of hMSH4-hMSH5 heterocomplex is a prerequisite for subsequent GPS2 recruitment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "DNA Repair (Amst) (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.dnarep.2005.07.004"}], "href": "https://doi.org/10.1016/j.dnarep.2005.07.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16122992"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16122992"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yen-Lin Chu, Xiling Wu, Yang Xu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "MutS homologues hMSH4 and hMSH5: diverse functional implications in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Biosci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2741/2112"}], "href": "https://doi.org/10.2741/2112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17127347"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17127347"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Béatrice Mandon-Pépin, Philippe Touraine, Frédérique Kuttenn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic investigation of four meiotic genes in women with premature ovarian failure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Endocrinol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1530/EJE-07-0400"}], "href": "https://doi.org/10.1530/EJE-07-0400"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18166824"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18166824"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Carolina Carlosama, Maëva Elzaiat, Liliana C Patiño, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Bi-allelic variants in DNA mismatch repair proteins MutS Homolog MSH4 and MSH5 cause infertility in both sexes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Reprod (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/humrep/deab230"}], "href": "https://doi.org/10.1093/humrep/deab230"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34755185"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34755185"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Arvand Akbari, Kimiya Padidar, Najmeh Salehi, et al. 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