Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines.
The gradual loss of DNA from the ends of telomeres has been implicated in the control of cellular proliferative potential. Telomerase is an enzyme that restores telomeric DNA sequences, and expression of its activity was thought to be essential for the immortalization of human cells, both in vitro and in tumor progression in vivo. Telomerase activity has been detected in 50-100% of tumors of different types, but not in most normal adult somatic tissues. It has also been detected in about 70% of human cell lines immortalized in vitro and in all tumor-derived cell lines examined to date. It has previously been shown that in vitro immortalized telomerase-negative cell lines acquire very long and heterogeneous telomeres in association with immortalization presumably via one or more novel telomere-lengthening mechanisms that we refer to as ALT (alternative lengthening of telomeres). Here we report evidence for the presence of ALT in a subset of tumor-derived cell lines and tumors. The maintenance of telomeres by a mechanism other than telomerase, even in a minority of cancers, has major implications for therapeutic uses of telomerase inhibitors.
Bryan
T M
TM
Children's Medical Research Institute, Sydney, NSW, Australia.
Englezou
A
A
Dalla-Pozza
L
L
Dunham
M A
MA
Reddel
R R
RR
D000328:Adult; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D015252:Deoxyribonucleases, Type II Site-Specific / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016615:Telomere / Q000648:ultrastructure; D014407:Tumor Cells, Cultured
D004254:DNA Nucleotidyltransferases; C059997:Hin recombinase; D019098:Telomerase; D015252:Deoxyribonucleases, Type II Site-Specific; C040158:GTAC-specific type II deoxyribonucleases