{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nGenetic studies have implicated MSH5 in maintaining genomic stability during immune diversification and reproductive development. In mouse models, deficiency of MSH5 and its obligate partner MSH4 alters immunoglobulin class switch recombination—evidenced by abnormal switch junctions with long microhomologies—and in human studies, certain MSH5 alleles have been linked to IgA deficiency and common variable immune deficiency. In parallel, mutations in MSH5 have been associated with premature ovarian failure, with both murine models and human pedigrees showing impaired DNA homologous recombination repair in ovarian cells. Moreover, altered expression of MSH5 by regulatory long noncoding RNAs further underscores its role in ovarian function and genome maintenance."}, {"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": "\nIn the context of meiosis, MSH5 functions as a critical component of the MSH4–MSH5 heterodimer that orchestrates the repair of programmed double‐strand breaks by binding to and stabilizing Holliday junctions. This heterocomplex forms sliding clamps that secure homologous chromosome interactions during meiotic recombination. Additional studies report that MSH5 interacts with proteins such as SMCY in testicular germ cells and that polymorphisms in MSH5 are associated with male infertility. Its broader role in DNA repair is further supported by findings that alternative splicing and non‐synonymous polymorphisms (for example, the P29S variant) impact its interaction with MSH4 and with other repair regulators such as GPS2."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in meiosis, MSH5 contributes to the repair of DNA damage in somatic cells. Notably, MSH5 localizes to the mitochondria where it binds mitochondrial DNA and interacts with components such as the Twinkle helicase and DNA polymerase γ, thereby promoting repair in response to oxidative stress. In addition, MSH5 facilitates homologous recombination repair at double‐strand breaks that arise during replication stress, enhancing cell survival after genotoxic challenges."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe activity of MSH5 is tightly regulated by its intracellular trafficking and protein stability. Studies demonstrate that MSH5 shuttles between the nucleus and cytoplasm via a CRM1‐dependent nuclear export signal, and that binding to partner proteins such as MSH4 can mask this export signal, thereby retaining MSH5 in the nucleus where it is less stable and more actively engaged in DNA repair. Disruption of these regulatory mechanisms—for instance, by the P29S variant—leads to altered protein–protein interactions and increased sensitivity to DNA damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, genome‐wide association studies have mapped the MSH5 locus (often in close proximity to BAT3) as a novel risk region in lung cancer, underscoring the clinical significance of MSH5 beyond its established roles in meiotic recombination and DNA repair."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hideharu Sekine, Ricardo C Ferreira, Qiang Pan-Hammarström, et al. 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