Expression of the MutL Homologue hMLH3 in Human Cells and its Role in DNA Mismatch Repair

Cannavó, Elda; Marra, Giancarlo; Sabates–Bellver, Jacob; Menigatti, Mirco; Lipkin, Steven M.; Fischer, Friedrich; Ćejka, Petr; Jiricny, Josef

doi:10.1158/0008-5472.can-05-2528

Cited by 111 publications

(154 citation statements)

References 34 publications

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“…This assumption originally suggested by results from the yeast studies (13) was recently supported by the study, in which a heterodimer of Mlh1 and Mlh3 was shown to contribute to mechanisms of tumour suppression in the mouse (14). Furthermore, a human homologue, hMutLÁ (hMLH1/ hMLH3) was shown with low efficiency to be able to repair mismatches in vitro (15). Since MMR occurs in the nucleus, to be functional in vivo, hMLH3 ought to localize in the nucleus.…”

Section: Introductionmentioning

confidence: 83%

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Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low-risk gene in HNPCC

Korhonen

Raevaara²,

Lohi³

et al. 2007

Oncol Rep

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Abstract. DNA mismatch repair (MMR) mechanism contributes to the maintenance of genomic stability. Loss of MMR function predisposes to a mutator cell phenotype, microsatellite instability (MSI) and cancer, especially hereditary non-polyposis colorectal cancer (HNPCC). To date, five MMR genes, hMSH2, hMSH6, hMLH1, hPMS2, and hMLH3 are associated with HNPCC. Although, hMLH3 is suggested to be causative in HNPCC, its relevance to MMR needs to be confirmed to reliably assess significance of the inherited sequence variations in it. Recently, a human heterodimer hMLH1/hMLH3 (hMutLÁ) was shown to be able to assist hMLH1/hPMS2 (hMutL·) in the repair of mismatches in vitro. To repair mismatches in vivo, hMLH3 ought to localize in the nucleus. Our immunofluorescence analyses indicated that when all the three MutL homologues are natively expressed in human cells, endogenous hMLH1 and hPMS2 localize in the nucleus, whereas hMLH3 stays in the cytoplasm. Absence of hPMS2 and co-expression of hMLH3 with hMLH1 results in its partial nuclear localization. Our results are clinically relevant since they show that in the nuclear localization hMLH3 is dependent on hMLH1 and competitive with hPMS2. The continuous nuclear localization of hMLH1 and hPMS2 suggests that in vivo, hPMS2 (hMutL·) has a major activity in MMR. In absence of hPMS2, hMLH3 (hMutLÁ) is located in the nucleus, suggesting a conditional activity in MMR and supporting its role as a low-risk gene in HNPCC.

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Section: Introductionmentioning

confidence: 83%

“…HeLa cells express hMLH3, hPMS2 and hMLH1, while HCT116 lacks hMLH1 and hPMS2 (15). HeLa cells were cultured in MEM + Earle's medium (Invitrogen/Gibco) and HCT116 cells in McCoy's 5a media (Invitrogen/Gibco) with 10% fetal bovine serum (Invitrogen/Gibco) at 37˚C in a 5% CO 2 -humidified atmosphere.…”

Section: Human Cell Linesmentioning

confidence: 99%

Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low-risk gene in HNPCC

Korhonen

Raevaara²,

Lohi³

et al. 2007

Oncol Rep

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“…The human MLH3 gene was first identified approximately in the year 2000, and it is located on 14q24.3 chromosome with a coding length of 4.3 kb, composed of 12 exons, of which exon 1 is 3.3 kb, accounting for 75 % of the coding region [3]. It is a member of a conserved protein family, which is involved in the DNA mismatch repair and meiotic recombination mechanism [4,5]. Furthermore, MLH3 was found to interact with MLH1 [12].…”

Section: Discussionmentioning

confidence: 99%

“…It was found on 14q24.3 chromosome with a coding length of 4.3 kb [3]. Its basic role is in the DNA mismatch repair mechanism, while it has been proposed to play a distinct role in the meiotic recombination mechanism [4,5]. Inactivation of the MLH3 gene has been suggested to play a role in both male and female infertility [3] since the presence of the MLH3 C2531T polymorphism leads to an increased risk for developing infertility [6].…”

Section: Introductionmentioning

confidence: 99%

Single-nucleotide polymorphism rs 175080 in the MLH3 gene and its relation to male infertility

Markandona

Dafopoulos

Anifandis

et al. 2015

J Assist Reprod Genet

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Purpose MLH3, a MutL homolog protein in mammals playing a role in DNA mismatch repair, is associated with spermatogenesis and male infertility. The purpose of the present study was to investigate the association of the singlenucleotide polymorphism (SNP), rs 175080 in the MLH3 gene, with sperm parameters in a Greek population. Methods The study included 300 men of couples undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) treatments (years 2011-2013). Genomic DNA was extracted from 300 peripheral blood samples, and conventional quantitative real-time PCR was performed for genotyping. Of them, 122 were from men used as Bcontrols^and 178 from men used as Bcases.^Allocation to the two groups was based on sperm concentrations (≥15 and <15 million/ml, respectively). Serum FSH, LH, estradiol, testosterone, and prolactin concentrations as well as sperm parameters were compared between three genotypes (GG, GA, and AA). Furthermore, the frequencies of these three genotypes were compared between Bcases^and Bcontrols.^R esults Anthropometric parameters and hormonal values did not differ significantly between the three genotypes. Significantly lower sperm concentrations were found in men with the AA genotype as compared to men with the GG and GA genotypes (p<0.001). The AA genotype had the lower progressive motility values as compared to the other two genotypes (p<0.05). Also, there was a significantly different distribution of the frequencies of the three genotypes between Bcases^and Bcontrols^(p<0.001). Conclusions It is suggested that the studied SNP in the MLH3 gene may be linked to oligozoospermia in Caucasian men of a certain area.

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“…Other MutL homologues, MutLβ (MLH1/PMS1) and MutLγ (MLH1/MLH3), are surmised to participate in the repair of some base-base mispairs and IDLs and may be partially redundant with MutLα (see (Cannavo et al, 2005).…”

Section: Mutation Avoidance and Post-replication Repairmentioning

confidence: 99%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

397

359

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DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

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Expression of the MutL Homologue hMLH3 in Human Cells and its Role in DNA Mismatch Repair

Cited by 111 publications

References 34 publications

Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low-risk gene in HNPCC

Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low-risk gene in HNPCC

Single-nucleotide polymorphism rs 175080 in the MLH3 gene and its relation to male infertility

DNA mismatch repair: Molecular mechanism, cancer, and ageing

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