Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repair.
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-beta 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 malignancies. 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.
Prolla
T A
TA
Howard Hughes Medical Institute, and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Baker
S M
SM
Harris
A C
AC
Tsao
J L
JL
Yao
X
X
Bronner
C E
CE
Zheng
B
B
Gordon
M
M
Reneker
J
J
Arnheim
N
N
Shibata
D
D
Bradley
A
A
Liskay
R M
RM
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D000818:Animals; D002352:Carrier Proteins; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes; D004261:DNA Replication / Q000235:genetics; D004268:DNA-Binding Proteins; D004198:Disease Susceptibility; D005656:Fungal Proteins / Q000235:genetics*; D007414:Intestinal Neoplasms / Q000235:genetics*; D007422:Intestines / Q000033:anatomy & histology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D018895:Microsatellite Repeats; D000070976:Mismatch Repair Endonuclease PMS2; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009154:Mutation; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics; D009687:Nuclear Proteins; D009928:Organ Specificity; D011506:Proteins / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C501486:MLH1 protein, human; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; D011506:Proteins; D000251:Adenosine Triphosphatases; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D045643:DNA Repair Enzymes