Abstract
Mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germline of mismatch repair deficient Msh2 knock-out mice. Spontaneous mutation rates in homozygous Msh2 −/− males were significantly higher than those in isogenic wild-type ( Msh2 +/+) and heterozygous ( Msh2 +/−) mice. In contrast, the irradiated Msh2 −/− mice did not show any detectable increases in their mutation rate, whereas significant ESTR mutation induction was observed in the irradiated Msh2 +/+ and Msh2 +/− animals. Considering these data and the results of other publications, we propose that the Msh2-deficient mice possess a mutator phenotype in their germline and somatic tissues while the loss of a single Msh2 allele does not affect the stability of heterozygotes.
Highlights
Mismatch repair (MMR) is essential in the avoidance of mutations and maintenance of genome stability
Msh2+/+, Msh2+/- and Msh2-/- males were given whole-body acute irradiation of 1 Gy X-rays delivered at 0.6 Gy min-1 (Andrex SMART 225 machine) and mated to untreated BALB/c females 10 weeks post-irradiation, ensuring that the litters generated were conceived with sperm derived from irradiated As spermatogonia [12]
expanded simple tandem repeat (ESTR) mutation rates per locus in the germline of males were estimated by dividing the total number of mutations scored in the offspring by the total number of ESTR alleles
Summary
Mismatch repair (MMR) is essential in the avoidance of mutations and maintenance of genome stability. Given that MMR is involved in the removal of a variety of mismatched DNA pairs arising during replication and recombination, as well as those caused by oxidative stress and some mutagens, mutations inactivating this pathway often result in genomic instability and cancer predisposition [1]. We have analysed the germline effects of several DNA repair deficiencies on spontaneous and radiation-induced mutation rates at endogenous expanded simple tandem repeat (ESTR) DNA loci [9,10,11]. Given that MMR is involved in the repair of endogenous and exogenous DNA damage, ESTR mutation rates were established in the germline of non-exposed and irradiated mice
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