Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DMA mismatch repair
- 1 March 1998
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 18 (3), 276-279
- https://doi.org/10.1038/ng0398-276
Abstract
Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer (HNPCC; refs 1–5). An important role for DNA replication errors in colorectal tumorigenesis has been suggested by the finding of frequent alterations in the length of specific mononucleotide tracts within genes controlling cell growth, including TGF-β receptor type II (ref. 6), BAX (ref. 7) and APC (ref. 8). A broader role for MMR deficiency in human tumorigenesis is implicated by microsatellite instability in a fraction of sporadic tumours, including gastric, endometrial and colorectal malignancies9. To better define the role of individual MMR genes in cancer susceptibility and MMR functions, we have generated mice deficient for the murine homologues of the human genes MLH1, PMS1 and PMS2. Surprisingly, we find that these mice show different tumour susceptibilities, most notably, to intestinal adenomas and adenocarcinomas, and different mutational spectra. Our results suggest that a general increase in replication errors may not be sufficient for intestinal tumour formation and that these genes share overlapping, but not identical functions.Keywords
This publication has 22 references indexed in Scilit:
- Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing overNature Genetics, 1996
- Microsatellite instability and DNA mismatch repair in human cancerSeminars in Cancer Biology, 1996
- Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosisCell, 1995
- Inactivation of the Type II TGF-β Receptor in Colon Cancer Cells with Microsatellite InstabilityScience, 1995
- MLH1, PMS1, and MSH2 Interactions During the Initiation of DNA Mismatch Repair in YeastScience, 1994
- The molecular basis of nucleotide excision repair syndromesMutation Research, 1994
- Mutation of a mutL Homolog in Hereditary Colon CancerScience, 1994
- Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancerNature, 1994
- Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesisNature, 1993
- Genetic markers for quantitative mutagenesis studies in Chinese hamster ovary cells Characteristics of some recently developed selective systemsMutation Research, 1980