The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2

Kondo, Emiko

doi:10.1093/nar/29.8.1695

Cited by 111 publications

(89 citation statements)

References 36 publications

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“…A previous study performed with mouse proteins showed that Pms2 expressed alone does not reside in the nucleus because of impaired nuclear import and that dimerization of Mlh1 and Pms2 is essential and limits nuclear localization of MutL· (19). In human, hMLH1 interacts with 36 homologous amino acid residues within hPMS2, hMLH3 and hPMS1 (20) supporting the idea of their redundant function in MMR. So far, only hMutL· (hMLH1/hPMS2) was shown to be involved in human MMR (21).…”

Section: Discussionmentioning

confidence: 79%

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: Discussionmentioning

confidence: 79%

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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“…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]. This interaction seems to be essential for a direct role of the Mlh1-Mlh3 endonuclease activity in resolving recombination intermediates and in DNA mismatch repair [13].…”

Section: Discussionmentioning

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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“…These screens identified genes encoding proteins known to interact with MLH1, such as PMS1, MLH3 and MED1/MBD4 (Bellacosa et al, 1999;Raschle et al, 1999;Kondo et al, 2001). A yeast two-hybrid screen of normal human Mammary Gland Matchmaker cDNA library (Clontech) identified the carboxy terminus of the human c-MYC proto-oncogene as an interacting sequence.…”

Section: Yeast Two-hybrid Analysis Of Interactions Between Mlh1 and Cmentioning

confidence: 99%

“…C-MYC also fails to interact with N-terminal regions of MLH1 (amino acids 1-579; data not shown). The region of MLH1 that interacts with c-MYC overlaps with the region of MLH1 required for heterodimerization with other MutL homologues (amino acids 492-742 (Kondo et al, 2001)). …”

Section: Yeast Two-hybrid Analysis Of Interactions Between Mlh1 and Cmentioning

confidence: 99%

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Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX

et al. 2003

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MSH2 and MLH1 have a central role in correcting mismatches in DNA occurring during DNA replication and have been implicated in the engagement of apoptosis induced by a number of cytotoxic anticancer agents. The function of MLH1 is not clearly defined, although it is required for mismatch repair (MMR) and engagement of apoptosis after certain types of DNA damage. In order to identify other partners of MLH1 that may be involved in signalling MMR or apoptosis, we used human MLH1 in yeast two-hybrid screens of normal human breast and ovarian cDNA libraries. As well as known partners of MLH1 such as PMS1, MLH3 and MBD4, we identified the carboxy terminus of the human c-MYC protooncogene as an interacting sequence. We demonstrate, both in vitro by yeast two-hybrid and GST-fusion pulldown experiments, as well as in vivo by coimmunoprecipitation from human tumour cell extracts, that MLH1 interacts with the c-MYC protein. We further demonstrate that the heterodimeric partner of c-MYC, MAX, interacts with a different MMR protein, MSH2, both in vitro and in vivo. Using an inducible c-MYC-ERt fusion gene, we show that elevated c-MYC expression leads to an increased HGPRT mutation rate of Rat1 cells and an increase in the number of frameshift mutants at the HGPRT locus. The effect on HGPRT mutation rate is small (2-3-fold), but is consistent with deregulated c-MYC expression partially inhibiting MMR activity.

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The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2

Cited by 111 publications

References 36 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

Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX

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