Human Molecular Genetics, Vol 6, 921-926, Copyright © 1997 by Oxford University Press
TM Bryan, L Marusic, S Bacchetti, M Namba and RR Reddel
According to the telomere hypothesis of senescence, the progressive
shortening of telomeres that occurs upon division of normal somatic cells
eventually leads to cellular senescence. The immortalisation of human cells
is associated with the acquisition of a telomere maintenance mechanism
which is usually dependent upon expression of the enzyme telomerase. About
one third of in vitro immortalised human cell lines, however, have no
detectable telomerase but contain telomeres that are abnormally long. The
nature of the alternative telomere maintenance mechanism (referred to as
ALT, for Alternative Lengthening of Telomeres) that must exist in these
telomerase-negative cells has not been elucidated. It has previously been
shown that abnormal lengthening of yeast telomeres may occur due to
mutations in the yeast telomerase RNA gene. That this is not the mechanism
of the abnormally long telomeres in ALT cell lines was demonstrated by the
finding that seven of seven ALT lines have wild-type human telomerase RNA
(hTR) sequence, including a novel polymorphism that is present in 30% of
normal individuals. We found that two ALT cell lines have no detectable
expression of the hTR gene. This shows that the ALT mechanism in these cell
lines is not dependent on hTR. Expression of exogenous hTR via infection of
these cells with a recombinant hTR-adenovirus vector did not result in
telomerase activity, indicating that their lack of telomerase activity is
not due to absence of hTR expression. We conclude that the ALT mechanism is
not dependent on the expression of hTR, and does not involve mutations in
the hTR sequence.
ARTICLES
The telomere lengthening mechanism in telomerase-negative immortal human cells does not involve the telomerase RNA subunit
Children's Medical Research Institute, Sydney, NSW, Australia.
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