INFLUENCE OF ATM FUNCTION ON TELOMERE METABOLISM

The ATM gene product, which is defective in the cancer-prone disorder ataxia telangiectasia, has been implicated in mitogenic signal transdu ction, chromosome condensation, meiotic recombination and cell cycle c ontrol. The ATM gene has homology with the TEL1 gene of yeast, mutatio ns of which lead to shortened telomeres. To test the hypothesis that t he ATM gene product is involved in telomere metabolism, we examined te lomeric associations (TA), telomere length, and telomerase activity in human cells expressing either dominant-negative or complementing frag ments of the ATM gene. The phenotype of RKO colorectal tumor cells exp ressing ATM fragments containing a leucine zipper (LZ) motif mimics th at of ataxia telangiectasia (A-T) cells. These transfected RKO cells r elative to transfected controls had a higher frequency of cells with T A and shortened telomeres, but no detectable change in telomerase acti vity. In addition, the percentage of cells with TA after gamma irradia tion was higher in the transfected RKO cells with dominant negative ac tivity of the ATM gene, compared to control cells. SV40 transformed fi broblasts derived from an A-T patient and transfected with a complemen ting carboxyl terminal kinase region of the ATM gene had a reduced fre quency of cells with TA, with no effect on the telomere length or telo merase activity. The present studies using isogenic cells with manipul ated ATM function demonstrate a role for the ATM gene product in telom ere metabolism.