Alternative lengthening of telomeres: a telomerase independent route to cellular immortality
D. Broccoli
Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA
The limited self-renewal capacity of most human cell types that
contributes to aging is recapitulated in vitro by primary fibroblasts
that undergo replicative senescence. Stabilization of telomeric repeat
arrays is sufficient to bypass this process and confer the potential
for unlimited cellular division. This cellular immortality is also
critical for tumorigenesis, an escalating health problem as the average
age of the population increases. Telomerase activation is the common
mechanism used by stem cells and tumors for maintenance of telomeric
DNA. However, a subset of tumors and cell lines use a
telomerase-independent mechanism, termed Alternative Lengthening of
Telomeres (ALT), to sustain telomeric DNA. ALT provides a rescue
pathway tumor cells might activate to overcome the deleterious effects
of telomere attrition induced by inhibition of telomerase. Current
evidence suggests that ALT depends on telomeric recombination. The
tumor suppressor p53 negatively regulates recombination and telomere
maintenance by ALT correlates with mutational inactivation of p53.
Consistent with this, reintroduction of p53 into ALT cells results in
growth suppression via a mechanism that does not require changes in
gene expression but does require a direct interaction with the
telomeric complex and intact suppression of recombination function. In
addition, recent evidence indicates that, while ALT is also active in
mice, telomerase and ALT are not functionally equivalent. These data
suggest that although ALT may act as a substitute for telomerase with
respect to telomere maintenance, its effects on tumor progression may
be distinct.
Key words:
Alternative lengthening of telomeres, p53, recombination, telomerase
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