Telomerase, a cellular ribonucleoprotein (RNP) reverse transcriptase, is not detected in most normal human tissues but is almost universally expressed in human cancers. Telomerase is transcriptionally silenced during human development, except for a subset of cells in highly proliferative tissues such as the germ line, blood, skin, and intestine. Even in these tissues telomeres progressively shorten with increased age. It has generally been thought that the exclusive function of telomerase was to prevent telomere shortening, but recently a number of reports have suggested a role for telomerase in addition to maintaining telomere length. Results indicate that, even in the absence of limiting telomere length, added telomerase still promotes tumorigenesis and cell proliferation. No specific mechanism by which telomerase might do this has been proposed. We think it is premature to ascribe nontelomere maintenance functions to telomerase. Various caveats exist and specific controls still need to be addressed.
ALT EXPLANATIONS Unlike humans, inbred laboratory mouse strains possess long telomeres (see image opposite page) and, in early-generation telomerase-deficient mice, the telomere reserve is sufficient to prevent telomere-based checkpoint responses that might lead to growth arrest. The observation that neither the template-RNA (mTR) nor catalytic-telomerase (mTERT) knockout strains shows obvious premature aging or cancer-prone changes in early generations, suggests that neither component serves an essential nontelomere maintenance function.
The table on the opposite page outlines experiments indicating that telomerase may actively promote tumor growth and/or cell survival even when telomeres are sufficiently long. But each of these results could have alternate interpretations. Immortal cell lines with an alternative-lengthening-of-telomere (ALT) pathway appear to require telomerase for malignant transformation, for example. But telomerase-silent ALT tumors, as reviewed by Sandy Chang and Ron DePinho at Harvard, are in a constant state of crisis (with some very short and some very long telomeres).(1) TERT may simply function to elongate the shortest telomeres, thus removing their DNA-damage signaling activity and indirectly permitting better tumor growth by an entirely telomere-dependent mechanism.
ALT cells use a recombination-based pathway to maintain their telomeres. Robert Weinberg and colleagues showed that a human ALT immortal cell line was not tumorigenic when high levels of H-RAS were expressed, in contrast to a similar cell line that expressed wildtype telomerase and H-RAS and made robust tumors.(2) Stewart then showed expression of a catalytically...
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