Atm deficiency causes an increased frequency of intrachromosomal homologous recombination in mice

Ataxia telangiectasia (AT) patients have inactivating mutations in both cop ies of the ATM gene. The ATM protein that the gene encodes is involved in D NA double-strand break (DSB) recognition; in its absence, p53 response to D SBs is delayed and reduced. In addition, AT patients have a high propensity for cancer, and cells from these patients show chromosomal instability. He re, using an in vivo mouse model system with the pink-eyed unstable mutatio n, we demonstrate that the absence of functional Atm results in a significa ntly elevated frequency of intrachromosomal recombination resulting in dele tion events (wild-type 17.73%, heterozygous Atm 15.72%, and mutant Atm 30.3 3%), No such increase was observed in mice heterozygous for Atm. These resu lts further advocate the role of ATM in maintaining genomic integrity after the onset of endogenous damage. This system relies on the initiation of ev ents during a relatively short time frame to produce an observable deletion product. AT patients have a lifelong exposure to endogenous damage and per haps similarly acting external agents, Because 25% of our genome consists o f repeated elements, genomic instability due to an increased level of homol ogous recombination between such repeats, as observed here, may contribute to carcinogenesis in AT patients.