Lack of DNA mismatch repair protein MSH6 in the rat results in hereditary non-polyposis colorectal cancer-like tumorigenesis.
To understand genetic instability in relation to tumorigenesis, experimental animal models have proven very useful. The DNA mismatch repair (MMR) machinery safeguards genomic integrity by repairing mismatches, insertion or deletion loops and responding to genotoxic agents. Here, we describe the functional characterization of a novel rat mutant model in which the MMR gene Msh6 has been genetically inactivated by N-ethyl-N-nitrosourea-driven target-selected mutagenesis. This model shows a robust mutator phenotype that is reflected by microsatellite instability and an increased germ line point mutation frequency. Consequently, these rats develop a spectrum of tumors with a high similarity to atypical hereditary non-polyposis colorectal cancer in humans. The MSH6 knockout rat complements existing models for studying genetic instable tumorigenesis as it provides experimental opportunities that are not available or suboptimal in current models.
van Boxtel
Ruben
R
Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
Toonen
Pim W
PW
van Roekel
Henk S
HS
Verheul
Mark
M
Smits
Bart M G
BM
Korving
Jeroen
J
de Bruin
Alain
A
Cuppen
Edwin
E
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000633:toxicity; D005838:Genotype; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D051381:Rats
D000477:Alkylating Agents; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D005038:Ethylnitrosourea