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Msh-2 suppresses in vivo mutation in a gene dose and lesion dependent manner

Sansom, Owen J., Toft, Neil J., Winton, Douglas J. and Clarke, Alan Richard 2001. Msh-2 suppresses in vivo mutation in a gene dose and lesion dependent manner. Oncogene 20 (27) , pp. 3580-3584. 10.1038/sj.onc.1204449

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Abstract

e deficient for the mismatch repair (MMR) gene Msh2 show accelerated tumourigenesis and a reduced apoptotic response to DNA damage of methylation type. Here we examine the effect of mutation for Msh2 on in vivo mutation frequencies in the intestine as determined by loss of function at the Dolichos biflorus (Dlb-1) locus. Spontaneous mutation frequencies were scored in cohorts of ageing mice either wild type or mutant for Msh2. In mice less than 1 year old, mutation frequencies were only elevated in Msh2 null mice. However, beyond this age heterozygous Msh2 mice showed significantly higher mutation frequencies than controls. These findings implicate a gene dose dependent requirement for Msh2 in mutation suppression and prompted an analysis of young Msh2 mutants following exposure to DNA damage. Following exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), Msh2 deficient mice show a reduced apoptotic response and an increase in mutation frequency. Heterozygotes did not differ from controls. Following exposure to cisplatin, no significant elevation was seen in mutation frequencies, even within homozygotes. This is particularly surprising given the association between cisplatin resistance and MMR deficiency. These findings therefore demonstrate a complex reliance upon functional Msh2 in mutation surveillance. We have identified three separate scenarios. First, where retention of both Msh2 alleles over an extended period of time appears critical to the suppression of spontaneous mutation; second, 3 weeks following exposure to MNNG, where only complete loss of Msh2 results in elevated mutation; and finally following cisplatin exposure, where induced levels of mutation are independent of Msh2 status.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > Q Science (General)
Q Science > QH Natural history > QH426 Genetics
Uncontrolled Keywords: Mismatch repair; apoptosis; mutation; heterozygosity; cisplatin; alkylation.
Publisher: Nature Publishing
ISSN: 0950-9232
Last Modified: 18 Jan 2018 21:07
URI: http://orca.cf.ac.uk/id/eprint/61377

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