{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMLH3 is a conserved DNA repair protein that acts predominantly in meiosis as part of the MutLγ complex (composed of MLH1–MLH3) to promote proper recombination and crossover formation. In human oocytes, MLH3—as well as its partner MLH1—marks late recombination nodules during pachynema, and heterogeneity in its localization has been implicated as a factor predisposing to aneuploidy. Consistent with its key role in gametogenesis, studies in both human and mouse models have linked MLH3 function and its genetic variants to spermatogenic efficiency and male fertility. Moreover, MLH3 appears to contribute, albeit in a less robust manner than the predominant MLH1–PMS2 complex, to meiotic recombination resolution by processing Holliday junctions and other joint molecule intermediates."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its meiotic function, MLH3 plays a supportive role in mismatch repair and homologous recombination in somatic cells. A number of biochemical reconstitution studies have demonstrated that MLH3—when engaged with its binding partners such as MutSβ or PCNA—exhibits endonucleolytic activity that specializes in nicking duplex DNA adjacent to recombination junctions. This activity is thought to contribute both to the proper resolution of DNA double-strand break repair intermediates and, under certain conditions, to the aberrant processing of secondary DNA structures leading to triplet repeat expansions associated with neurological disorders. Furthermore, when MLH3 is ectopically expressed or manipulated in cell‐based models, its recruitment to sites of DNA damage (even in the absence of the primary MutLα complex) underscores its potential as a backup or auxiliary endonuclease in recombination repair."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "13"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDespite its clear mechanistic roles in recombination and DNA repair, the contribution of MLH3 alterations to cancer predisposition remains nuanced. Although early studies explored germline mutations and polymorphisms in MLH3 with respect to colorectal, endometrial, cervical, and even breast cancers, most genetic and biochemical analyses indicate that MLH3 is a lower‐risk gene in hereditary non‐polyposis colorectal cancer and related tumor types. Nonetheless, altered MLH3 expression—as observed in promoter methylation patterns in low‐grade gliomas and down‐regulation in breast tumors—and subtle associations with cancer patient survival suggest that MLH3’s repair functions might indirectly impact tumor progression and genomic stability in diverse somatic contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "25"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michelle L Lenzi, Jenetta Smith, Timothy Snowden, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Extreme heterogeneity in the molecular events leading to the establishment of chiasmata during meiosis i in human oocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/427268"}], "href": "https://doi.org/10.1086/427268"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15558497"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15558497"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Cristina Ferrás, Xiao-lei Zhou, Mário Sousa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DNA mismatch repair gene hMLH3 variants in meiotic arrest."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Fertil Steril (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.fertnstert.2007.01.063"}], "href": "https://doi.org/10.1016/j.fertnstert.2007.01.063"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17482610"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17482610"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Nicole Charbonneau, Ravindra Amunugama, Christoph Schmutte, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evidence that hMLH3 functions primarily in meiosis and in hMSH2-hMSH3 mismatch repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cbt.8.14.8886"}], "href": "https://doi.org/10.4161/cbt.8.14.8886"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19483466"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19483466"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Keqian Xu, Tingting Lu, Hui Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of MSH5 C85T and MLH3 C2531T polymorphisms in the risk of male infertility with azoospermia or severe oligozoospermia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Chim Acta (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cca.2009.09.038"}], "href": "https://doi.org/10.1016/j.cca.2009.09.038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19808033"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19808033"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ourania Markandona, Konstantinos Dafopoulos, George Anifandis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Single-nucleotide polymorphism rs 175080 in the MLH3 gene and its relation to male infertility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Assist Reprod Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10815-015-0594-z"}], "href": "https://doi.org/10.1007/s10815-015-0594-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26520453"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26520453"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Elda Cannavo, Aurore Sanchez, Roopesh Anand, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of the MLH1-MLH3 endonuclease in meiosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-020-2592-2"}], "href": "https://doi.org/10.1038/s41586-020-2592-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32814904"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32814904"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Shoaib Nawaz, Muhammad Imran Ullah, Beenish Samreen Hamid, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A loss-of-function variant in DNA mismatch repair gene MLH3 underlies severe oligozoospermia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hum Genet (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s10038-021-00907-z"}], "href": "https://doi.org/10.1038/s10038-021-00907-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33517345"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33517345"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ravi R Iyer, Anna Pluciennik, Jochen Genschel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.104125"}], "href": "https://doi.org/10.1074/jbc.M110.104125"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20154325"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20154325"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Lennart M Roesner, Christian Mielke, Silke Fähnrich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Stable expression of MutLγ in human cells reveals no specific response to mismatched DNA, but distinct recruitment to damage sites."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.24591"}], "href": "https://doi.org/10.1002/jcb.24591"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23696135"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23696135"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Anasheh Halabi, Kayla T B Fuselier, Ed Grabczyk "}, {"type": "b", "children": [{"type": "t", "text": "GAA•TTC repeat expansion in human cells is mediated by mismatch repair complex MutLγ and depends upon the endonuclease domain in MLH3 isoform one."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gky143"}], "href": "https://doi.org/10.1093/nar/gky143"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29529236"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29529236"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Xinyan Zhao, Chunlan Mu, Jia Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The association of four SNPs in DNA mismatch repair genes with idiopathic male infertility in northwest China."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Immunogenet (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/iji.12448"}], "href": "https://doi.org/10.1111/iji.12448"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31342644"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31342644"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Lyudmila Y Kadyrova, Vaibhavi Gujar, Vickers Burdett, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human MutLγ, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1914718117"}], "href": "https://doi.org/10.1073/pnas.1914718117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32015124"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32015124"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Md Maminur Rahman, Mohiuddin Mohiuddin, Islam Shamima Keka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic evidence for the involvement of mismatch repair proteins, PMS2 and MLH3, in a late step of homologous recombination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA120.013521"}], "href": "https://doi.org/10.1074/jbc.RA120.013521"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33453991"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33453991"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Tuija Hienonen, Päivi Laiho, Reijo Salovaara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Little evidence for involvement of MLH3 in colorectal cancer predisposition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.11218"}], "href": "https://doi.org/10.1002/ijc.11218"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12800209"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12800209"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Mirjam M de Jong, Robert M W Hofstra, Krista A Kooi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "No association between two MLH3 variants (S845G and P844L)and colorectal cancer risk."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Genet Cytogenet (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cancergencyto.2003.10.008"}], "href": "https://doi.org/10.1016/j.cancergencyto.2003.10.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15193445"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15193445"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Honglin Song, Susan J Ramus, Lydia Quaye, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common variants in mismatch repair genes and risk of invasive ovarian cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgl089"}], "href": "https://doi.org/10.1093/carcin/bgl089"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16774946"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16774946"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Nicholas P Taylor, Matthew A Powell, Randall K Gibb, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MLH3 mutation in endometrial cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-06-0248"}], "href": "https://doi.org/10.1158/0008-5472.CAN-06-0248"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16885347"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16885347"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Mari K Korhonen, Tiina E Raevaara, Hannes Lohi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low-risk gene in HNPCC."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2007)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17203173"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17203173"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Mari K Korhonen, Elina Vuorenmaa, Minna Nyström "}, {"type": "b", "children": [{"type": "t", "text": "The first functional study of MLH3 mutations found in cancer patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Chromosomes Cancer (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/gcc.20581"}], "href": "https://doi.org/10.1002/gcc.20581"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18521850"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18521850"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Thibaud Koessler, Elizabeth M Azzato, Barbara Perkins, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common germline variation in mismatch repair genes and survival after a diagnosis of colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.24120"}], "href": "https://doi.org/10.1002/ijc.24120"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19115210"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19115210"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Jianghua Ou, Merete Rasmussen, Helga Westers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Chromosomes Cancer (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/gcc.20644"}], "href": "https://doi.org/10.1002/gcc.20644"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19156873"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19156873"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Feng Ye, Qi Cheng, Jiajie Shen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mismatch repair gene MLH3 Pro844Leu and Thr942Ile polymorphisms and the susceptibility to cervical carcinoma and HPV infection: a case-control study in a Chinese population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0096224"}], "href": "https://doi.org/10.1371/journal.pone.0096224"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24759751"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24759751"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Halka Lhotska, Zuzana Zemanova, Hana Cechova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic and epigenetic characterization of low-grade gliomas reveals frequent methylation of the MLH3 gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Chromosomes Cancer (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/gcc.22266"}], "href": "https://doi.org/10.1002/gcc.22266"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26303387"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26303387"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Celina Faig Lima Carta, Mônica Ghislaine Oliveira Alves, Patrícia Pimentel de Barros, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Screening methylation of DNA repair genes in the oral mucosa of chronic smokers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Oral Biol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.archoralbio.2018.04.017"}], "href": "https://doi.org/10.1016/j.archoralbio.2018.04.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29775861"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29775861"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Rozhgar A Khailany, Mehmet Ozaslan "}, {"type": "b", "children": [{"type": "t", "text": "Exonic sequencing and MLH3 gene expression analysis of breast cancer patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Biol (Noisy-le-grand) (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.14715/cmb/2021.67.3.5"}], "href": "https://doi.org/10.14715/cmb/2021.67.3.5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34933735"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34933735"}]}]}]}