Regulation of the hTERT telomerase catalytic subunit by the c-Abl tyrosinekinase

Background: Telomeres consist of repetitive (TTAGGG) DNA sequences that are maintained by the multisubunit telomerase ribonucleoprotein. Telomerase co nsists of an RNA, which serves as template for the sequence tracts, and a c atalytic subunit that functions in reverse transcription of the RNA templat e. Cloning and characterization of the human catalytic subunit of telomeras e (hTERT) has supported a role in cell transformation. How telomerase activ ity is regulated, however, is largely unknown. Results: We show here that hTERT associates directly with the c-Abl protein tyrosine kinase. We also found that c-Abl phosphorylates hTERT and inhibit s hTERT activity. Moreover, our findings demonstrate that exposure of cells to ionizing radiation induces tyrosine phosphorylation of hTERT by a c-Abl -dependent mechanism. The functional significance of the c-Abl-hTERT intera ction is supported by the demonstration that cells deficient in c-Abl show telomere lengthening. Conclusions: The ubiquitously expressed c-Abl tyrosine kinase is activated by DNA double-strand breaks. Our finding of telomere lengthening in c-Abl-d eficient cells and the functional interactions between c-Abl and hTERT supp ort a role for c-Abl in the regulation of telomerase function.