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Exonerating Telomerase

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Posted 07 May 2006 - 08:51 AM

A recent study reported on a new way by which telomerase mediates its role in genomic stability. Essentially, it was found that telomerase has a mitochondrial targeting sequence [MTS (a way by which the cell can direct proteins to mitochondria)] and that its function in mitochondria was to make them more sensitive to oxidising molecules by inducing apoptosis. In fact, when the MTS in telomerase was experimentally disabled so that telomerase was prevented from entering mitochondria, cells were observed to be increasingly resistant to oxidant mediated apoptosis.

Initially, this function may seem paradoxical, yet it makes sense in cells with unlimited mitotic potential (able to divide indefinitely). In these cells, which include germ line and stem cells, a genomic mutation caused by oxidants from a malfunctioning mitochondrion could be propagated for the lifespan of the organism and potentially indefinately in the germ line. Therefore coupling the enxyme responsible for unlimited dividing potential - telomerase - to an increased level of quality control is a sensible evolutionary function.

If telomerase cannot enter mitochondria to perform its strict quality control, however, we potentially have a cell that whilst able to divide forever can also rapidly accrue mitochondrially generated mutagenic oxidants. Interestingly, a "switch" was discovered that regulated the ability of telomerase to leave its nuclear home so that it can localize to mitochondria and provide its quality control function. It would follow that if one could decrease oxidant concentration that less telomerase would be directed to mitochondria and another study reported precisely that.

Therefore, it may well be time to rethink the notion that telomerase is directly coupled to cancer and instead examine the role of proteins and mechanisms associated with facillitating the transport of telomerase into mitochondria.

The implications for WILT/SENS, for the treatment of cancer and for placing telomerase back on the longevity map are considerable.

#2 John Schloendorn

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Posted 07 May 2006 - 05:43 PM

Your interpretation seems to make a lot of sense.

I'm not sure if I buy into the requirement for catalytic activity of telomerase though. It seems that one would need to know more about the mechanism of the mutant to conclude that it *specifically* ablates catalytic activity and does nothing else.

Also, I wonder if the same mechanism is operational in more cancer-prone cells such as adult stem cells.

If so, then in the context of WILT, switching off this potential tumor-suppressor pathway as a side-effect might actually be beneficial, because it would presumably increase cell survival, which is sorely needed in WILT. In the dream scenario, this would not come at the cost of increased tumorigenicity, because WILT would prevent all tumors.

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