MLH3

A DNA mismatch repair gene associated with mammalian microsatellite instability

Steven M. Lipkin, Victoria Wang, Russell Jacoby, Sharmila Banerjee-Basu, Andreas D. Baxevanis, Henry T. Lynch, Rosemary M. Elliott, Francis S. Collins

Research output: Contribution to journalArticle

242 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)27-35
Number of pages9
JournalNature Genetics
Volume24
Issue number1
DOIs
StatePublished - 2000

Fingerprint

Microsatellite Instability
DNA Mismatch Repair
Colonic Neoplasms
Genes
Congenic Mice
Plant Proteins
Mutation
Proteins
Fungal Proteins
Conserved Sequence
Nuclear Proteins
Open Reading Frames
Organism Cloning
Colon
Epithelium
Cell Culture Techniques
Bacteria
Neoplasms

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)
  • Genetics

Cite this

Lipkin, S. M., Wang, V., Jacoby, R., Banerjee-Basu, S., Baxevanis, A. D., Lynch, H. T., ... Collins, F. S. (2000). MLH3: A DNA mismatch repair gene associated with mammalian microsatellite instability. Nature Genetics, 24(1), 27-35. https://doi.org/10.1038/71643

MLH3 : A DNA mismatch repair gene associated with mammalian microsatellite instability. / Lipkin, Steven M.; Wang, Victoria; Jacoby, Russell; Banerjee-Basu, Sharmila; Baxevanis, Andreas D.; Lynch, Henry T.; Elliott, Rosemary M.; Collins, Francis S.

In: Nature Genetics, Vol. 24, No. 1, 2000, p. 27-35.

Research output: Contribution to journalArticle

Lipkin, SM, Wang, V, Jacoby, R, Banerjee-Basu, S, Baxevanis, AD, Lynch, HT, Elliott, RM & Collins, FS 2000, 'MLH3: A DNA mismatch repair gene associated with mammalian microsatellite instability', Nature Genetics, vol. 24, no. 1, pp. 27-35. https://doi.org/10.1038/71643
Lipkin, Steven M. ; Wang, Victoria ; Jacoby, Russell ; Banerjee-Basu, Sharmila ; Baxevanis, Andreas D. ; Lynch, Henry T. ; Elliott, Rosemary M. ; Collins, Francis S. / MLH3 : A DNA mismatch repair gene associated with mammalian microsatellite instability. In: Nature Genetics. 2000 ; Vol. 24, No. 1. pp. 27-35.
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