MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability

Abstract

DNA mismatch repair is important because of its role in maintaining genomic integrity and its association with hereditary non-polyposis colon cancer (HNPCC). To identify new human mismatch repair proteins, we probed nuclear extracts with the conserved carboxy-terminal MLH1 interaction domain. Here we describe the cloning and complete genomic sequence of MLH3, which encodes a new DNA mismatch repair protein that interacts with MLH1. MLH3 is more similar to mismatch repair proteins from yeast, plants, worms and bacteria than to any known mammalian protein, suggesting that its conserved sequence may confer unique functions in mice and humans. Cells in culture stably expressing a dominant-negative MLH3 protein exhibit microsatellite instability. Mlh3 is highly expressed in gastrointestinal epithelium and physically maps to the mouse complex trait locus colon cancer susceptibility I (Ccs1). Although we were unable to identify a mutation in the protein-coding region of Mlh3 in the susceptible mouse strain, colon tumours from congenic Ccs1 mice exhibit microsatellite instability. Functional redundancy among Mlh3, Pms1 and Pms2 may explain why neither Pms1 nor Pms2 mutant mice develop colon cancer, and why PMS1 and PMS2 mutations are only rarely found in HNPCC families.

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

“…It is probable that the A allele has a deteriorating effect in spermatogenesis, which is further amplified in a homozygotic condition. 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].…”

“…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].…”

“…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]. Human MLH3 (hMLH3) gene may also be associated to spermatogenesis and male infertility, while MLH3-MLH1 pathway seems to play a key role in making crossovers during mammalian meiosis [7] since it appears that this pathway directs an unknown factor that resolves Holliday junction and intermediates into crossovers [8].…”

Les homologues de MutS et de MutL au cours de la méiose chez les mammifères

“…En revanche, différents travaux permettent de proposer aujourd'hui que l'homologue de MutL impliqué avec MLH1 dans la formation des crossing-over, est la protéine MLH3 (Figure 2). Cette protéine, récemment identifiée chez l'homme [16], était un candidat intéressant dans la mesure où, chez Saccharomyces cerevisiae, elle participe aux mécanismes de recombinaison méiotique [12]. Il a été récemment montré que le gène MLH3 est exprimé dans les cellules méiotiques de souris et dans le testicule chez l'homme [17].…”

“…Il en résulte un blocage de la gamétogenèse et une stérilité. Par ailleurs, il a été montré que les protéines MLH1 et MLH3 interagissent [16] et qu'elles sont co-localisées sur les chromosomes méiotiques en fin de prophase. L'ensemble de ces résultats suggère que MSH4, en fin de prophase, est associé à l'hétérodimère MLH1-MLH3, qui est impliqué dans la formation des crossing-over.…”