Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene  Pms2

Abstract

The Pms2 gene has been implicated in hereditary colon cancer and is one of several mammalian homologs of the Escherichia coli mutL DNA mismatch repair gene. To determine the effect of Pms2 inactivation on genomic integrity in vivo, hybrid transgenic mice were constructed that carry targeted disruptions at the Pms2 loci along with a chromosomally integrated mutation reporter gene. In the absence of any mutagenic treatment, mice nullizygous for Pms2 showed a 100-fold elevation in mutation frequency in all tissues examined compared with both wild-type and heterozygous litter mates. The mutation pattern in the nullizygotes was notable for frequent 1-bp deletions and insertions within mononucleotide repeat sequences, consistent with an essential role for PMS2 in the repair of replication slippage errors. Further, the results demonstrate that high rates of mutagenesis in multiple tissues are compatible with normal development and life and are not necessarily associated with accelerated aging. Also, the finding of genetic instability in all tissues tested contrasts with the limited tissue distribution of cancers in the animals, raising important questions regarding the role of mutagenesis in carcinogenesis.

Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT

“…PMS2 7/7 mice showed destabilized microsatellite DNA sequences and a 100-fold elevation in mutation frequency in all tissues examined compared with both wild-type and heterozygous litter mates even in the absence of mutagen treatment (Baker et al, 1995(Baker et al, , 1996Narayanan et al, 1997;Prolla et al, 1998). Our results indicate that PMS2-de®cient mice are hypersensitive to thymic lymphoma induction by MNU.…”

Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice

“…Recently, PMS2 de®cient mice carrying a supF reporter gene were analysed (Narayanan et al, 1997). The mutation frequency of supF/PMS2 7/7 mice was approximately 25 ± 100-fold higher than normal, substantially higher than the lacI/MSH2 7/7 mutation frequency.…”

Identification of hMutLβ, a Heterodimer of hMLH1 and hPMS1

“…Such an altered mutation spectrum might lead to the inactivation of different tumor suppressor genes and thus, in turn, to a different tumor spectrum. Initially, the likelihood of this happening appeared to be low, as both MLH1-and PMS2-deficient mice showed a high degree of microsatellite instability (43) and all the tested tissues displayed an approximately 100-fold increase in mutation rates (44). However, recent detailed analysis of the above knock-out mouse models have shown that the mutator phenotype in microsatellites of Mlh1Ϫ/Ϫ mice is 2-3-fold higher than that of Pms2Ϫ/Ϫ animals (45), suggesting that the loss of the latter gene does not completely inactivate the repair of IDLs.…”