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[Cancer Research 60, 395-399, January 15, 2000]
© 2000 American Association for Cancer Research

Molecular Biology and Genetics

Atm Deficiency Causes an Increased Frequency of Intrachromosomal Homologous Recombination in Mice1

Alexander J. R. Bishop, Carrolee Barlow, Anthony J. Wynshaw-Boris and Robert H. Schiestl2

Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115 [A. J. R. B., R. H. S]; Genetic Disease Research Branch, National Genome Research Institute, NIH, Bethesda, Maryland 20892 [C. B., A. J. W-B.]; The Salk Institute for Biological Studies, La Jolla, California 92037 [C. B.]; and University of California, San Diego School of Medicine, La Jolla, California 92093 [A. J. W-B.]

Ataxia telangiectasia (AT) patients have inactivating mutations in both copies of the ATM gene. The ATM protein that the gene encodes is involved in DNA double-strand break (DSB) recognition; in its absence, p53 response to DSBs is delayed and reduced. In addition, AT patients have a high propensity for cancer, and cells from these patients show chromosomal instability. Here, using an in vivo mouse model system with the pink-eyed unstable mutation, we demonstrate that the absence of functional Atm results in a significantly elevated frequency of intrachromosomal recombination resulting in deletion events (wild-type 17.73%, heterozygous Atm 15.72%, and mutant Atm 30.33%). No such increase was observed in mice heterozygous for Atm. These results further advocate the role of ATM in maintaining genomic integrity after the onset of endogenous damage. This system relies on the initiation of events during a relatively short time frame to produce an observable deletion product. AT patients have a lifelong exposure to endogenous damage and perhaps similarly acting external agents. Because 25% of our genome consists of repeated elements, genomic instability due to an increased level of homologous recombination between such repeats, as observed here, may contribute to carcinogenesis in AT patients.




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