Regulation of the hTERT telomerase catalytic subunit by the c-Abl tyrosine kinase.
BACKGROUND
Telomeres consist of repetitive (TTAGGG) DNA sequences that are maintained by the multisubunit telomerase ribonucleoprotein. Telomerase consists of an RNA, which serves as template for the sequence tracts, and a catalytic subunit that functions in reverse transcription of the RNA template. Cloning and characterization of the human catalytic subunit of telomerase (hTERT) has supported a role in cell transformation. How telomerase activity 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 inhibits 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 interaction 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-deficient cells and the functional interactions between c-Abl and hTERT support a role for c-Abl in the regulation of telomerase function.
Kharbanda
S
S
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Kumar
V
V
Dhar
S
S
Pandey
P
P
Chen
C
C
Majumder
P
P
Yuan
Z M
ZM
Whang
Y
Y
Strauss
W
W
Pandita
T K
TK
Weaver
D
D
Kufe
D
D
D020134:Catalytic Domain; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005347:Fibroblasts; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015151:Immunoblotting; D010766:Phosphorylation; D011233:Precipitin Tests; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D012313:RNA; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*; D016615:Telomere / Q000502:physiology; D014162:Transfection
D004268:DNA-Binding Proteins; C422952:telomerase RNA; D012313:RNA; D016315:Proto-Oncogene Proteins c-abl; D019098:Telomerase