Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent.
The mutational response of mismatch repair-deficient animals to the alkylating agent N-methyl-N-nitrosourea was evaluated by using a transgenic lacI reporter system. Although the mutations detected in MSH2 heterozygotes were similar to those of controls, MSH2-/- animals demonstrated striking increases in mutation frequency in response to this agent. G:C to A:T transitions at GpG sites, as opposed to CpG sites, dominated the mutational spectrum of both MSH2+/+ and MSH2-/- N-methyl-N-nitrosourea -treated animals. Extrapolating to humans with hereditary non-polyposis colorectal cancer, the results suggest that MSH2 heterozygotes are unlikely to be at increased risk of mutation, even when exposed to potent DNA methylating agents. In contrast, mismatch repair-deficient cells spontaneously arising within individuals with hereditary non-polyposis colorectal cancer would likely exhibit hypermutability in response to such mutagens, an outcome predicted to accelerate the pace of tumorigenesis.
Andrew
S E
SE
Centre for Molecular Medicine and Therapeutics, and Department of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3.
McKinnon
M
M
Cheng
B S
BS
Francis
A
A
Penney
J
J
Reitmair
A H
AH
Mak
T W
TW
Jirik
F R
FR
D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D008770:Methylnitrosourea / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D051718:MutS Homolog 2 Protein; D016296:Mutagenesis; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics
D000477:Alkylating Agents; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D008770:Methylnitrosourea; D004247:DNA; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein