Telomerase-independent cytoprotection by TERT

Telomerase is a ribonucleoprotein: the RNA component (TERC) provides the template information, and the protein component (TERT in humans) catalyzes polymerization of new telomeric DNA. Both are essential to the activity of the enzyme — at least, insofar as production of telomeres is concerned. Lee et al. report that TERT alone protects cells from multiple types of potentially lethal stresses, even in the absence of TERC:

TERT promotes cellular and organismal survival independently of telomerase activity

The expression level of the telomerase catalytic subunit (telomerase reverse transcriptase, TERT) positively correlates with cell survival after exposure to several lethal stresses. However, whether the protective role of TERT is independent of telomerase activity has not yet been clearly explored. Here, we genetically evaluated the protective roles of both TERT and telomerase activity against cell death induced by staurosporine (STS) and N-methyl-d-aspartic acid (NMDA). First generation (G1) TERT-deficient mouse embryonic fibroblasts (MEFs) displayed an increased sensitivity to STS, while TERT transgenic MEFs were more resistant to STS-induced apoptosis than wild-type. Deletion of the telomerase RNA component (TERC) failed to alter the sensitivity of TERT transgenic MEFs to STS treatment. Similarly, NMDA-induced excitotoxic cell death of primary neurons was suppressed by TERT, but not by TERC both in vitro and in vivo. Specifically, NMDA accelerated death of TERT-deficient mice, while TERT transgenic mice showed enhanced survival when compared with wild-type littermates after administration of NMDA. In addition, the transgenic expression of TERT protected motor neurons from apoptosis induced by sciatic nerve axotomy. These results indicate that telomerase activity is not essential for the protective function of TERT. This telomerase activity-independent TERT function may contribute to cancer development and aging independently of telomere lengthening.

Note that two of the cell types studied (primary and motor neurons) are entirely post-mitotic — which underscores the novelty of TERT’s new function (though it’s certainly possible that a catalytic function of telomerase could play a role in a postmitotic lineage). For more on the subject of excitotoxic cell death see Robert Sapolsky’s old chestnut Stress, the Aging Brain, and the Mechanisms of Neuron Death.

The obvious next step is to “bash” the TERT protein, introducing target mutations and asking which parts of the protein one can break and still preserve the cytoprotective function. Will the critical region map to the catalytic center? Given the TERC-independence of the phenomenon, it’s doubtful, but stranger things have happened.


One comment

  1. has a telomerase inhibitor that binds tightly to the RNA template of telomerase. It would seem that the inhibiting molecule, “GRN163L” by its very presence on the template, could inhibit the some aspects of the whole molecule. Feel free to contact me at my email address.

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