| mutL homolog 1 | OKDB#: 85 |
| Symbols: | MLH1 | Species: | human | ||
| Synonyms: | FCC2, COCA2, HNPCC, hMLH1, HNPCC2, MMRCS1 | Locus: | 3p22.2 in Homo sapiens |
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| General Comment |
Mammalian mismatch repair proteins belonging to the MutLHS system play an essential role in the repair of replication errors during meiosis. Germline mutations in this class of repair genes lead to genetic predisposition to colon cancer - hereditary non-polyposis colon cancer type 2 (HNPCC2) (Edelmann et al. 1999).
Oocyte-Specific Differences in Cell-Cycle Control Create an Innate Susceptibility to Meiotic Errors. Nagaoka SI et al. Segregation of homologs at the first meiotic division (MI) is facilitated by crossovers and by a physical constraint imposed on sister kinetochores that facilitates monopolar attachment to the MI spindle. Recombination failure or premature separation of homologs results in univalent chromosomes at MI, and univalents constrained to form monopolar attachments should be inherently unstable and trigger the spindle assembly checkpoint (SAC) [1]. Although univalents trigger cell-cycle arrest in the male [2-5], this is not the case in mammalian oocytes [6, 7]. Because the spindle assembly portion of the SAC appears to function normally [8-10], two hypotheses have been proposed to explain the lack of response to univalents: (1) reduced stringency ofthe oocyte SAC to aberrant chromosome behavior [7], and (2) the ability of univalents to satisfy the SAC by forming bipolar attachments [6]. The present study of Mlh1 mutant mice demonstrates that metaphase alignment is not a prerequisite for anaphase onset and provides strong evidence that MI spindle stabilization and anaphase onset require stable bipolar attachment of a critical mass-but not all-of chromosomes. We postulate that subtle differences in SAC-mediated control make the human oocyte inherently error prone and contribute to the age-related increase in aneuploidy.
NCBI Summary: The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017] |
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| General function | Cell death/survival, Cell cycle regulation, DNA Replication, Tumor suppressor, DNA repair | ||||
| Comment | Examination of meiosis in MLH1-deficient males reveals that the cells enter meiotic prophase and arrest at pachytene. These mice possess not only microsatellite instability but are also infertile (both males and females). Mlh1 appears to localize to sites of crossing over on meiotic chromosomes. Together these findings suggest that Mlh1 is involved in DNA mismatch repair and meiotic crossing over (Baker et al, 1996; Edelmann et al, 1996) | ||||
| Cellular localization | Nuclear | ||||
| Comment | |||||
| Ovarian function | Oogenesis, Oocyte maturation | ||||
| Comment | Failure to recombine is a common feature of human oogenesis. Hassold T et al. (2020) Failure of homologous chromosomes to recombine is arguably the most important cause of human meiotic nondisjunction, having been linked to numerous autosomal and sex chromosome trisomies of maternal origin. However, almost all information on these "exchangeless" homologs has come from genetic mapping studies of trisomic conceptuses, so the incidence of this defect and its impact on gametogenesis are not clear. If oocytes containing exchangeless homologs are selected against during meiosis, the incidence may be much higher in developing germ cells than in zygotes. To address this, we initiated studies of exchangeless chromosomes in fetal ovarian samples from elective terminations of pregnancy. In total, we examined more than 7,000 oocytes from 160 tissue samples, scoring for the number of foci per cell of the crossover-associated protein MLH1. We identified a surprisingly high level of recombination failure, with more than 7% of oocytes containing at least one chromosome pair that lacked an MLH1 focus. Detailed analyses indicate striking chromosome-specific differences, with a preponderance of MLH1-less homologs involving chromosomes 21 or 22. Further, the effect was linked to the overall level of recombination in the cell, with the presence of one or two exchangeless chromosomes in a cell associated with a 10%-20% reduction in the total number of crossovers. This suggests individuals with lower rates of meiotic recombination are at an increased risk of producing aneuploid offspring.////////////////// | ||||
| Expression regulated by | |||||
| Comment | |||||
| Ovarian localization | Oocyte | ||||
| Comment | Meiotic recombination in human oocytes. Cheng EY et al. Studies of human trisomies indicate a remarkable relationship between abnormal meiotic recombination and subsequent nondisjunction at maternal meiosis I or II. Specifically, failure to recombine or recombination events located either too near to or too far from the centromere have been linked to the origin of human trisomies. It should be possible to identify these abnormal crossover configurations by using immunofluorescence methodology to directly examine the meiotic recombination process in the human female. Accordingly, we initiated studies of crossover-associated proteins (e.g., MLH1) in human fetal oocytes to analyze their number and distribution on nondisjunction-prone human chromosomes and, more generally, to characterize genome-wide levels of recombination in the human female. Our analyses indicate that the number of MLH1 foci is lower than predicted from genetic linkage analysis, but its localization pattern conforms to that expected for a crossover-associated protein. In studies of individual chromosomes, our observations provide evidence for the presence of 'vulnerable' crossover configurations in the fetal oocyte, consistent with the idea that these are subsequently translated into nondisjunctional events in the adult oocyte. | ||||
| Follicle stages | |||||
| Comment | |||||
| Phenotypes |
POF (premature ovarian failure) |
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| Mutations |
4 mutations
Species: mouse
Species: mouse
Species: D. melanogaster
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
| Links |
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| created: | July 22, 1999, midnight | by: |
Hsueh email:
home page: |
| last update: | Dec. 16, 2020, 9:11 p.m. | by: | hsueh email: |
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