From: Aubrey de Grey (ag24@gen.cam.ac.uk)
Date: Mon Sep 15 2003 - 06:18:02 MDT
Robert Bradbury wrote:
> Aubrey, my readings right now suggest that the ALT pathway for
> the extension of telomeres (or at least part of the ALT pathway)
> involves homologous recombination repair between telomeres.
Correct.
> It makes sense since telomeres are essentially identical and so
> it is difficult to prevent short telomere from using a longer
> telomere as a repair substrate. If so it is going to be hard
> to deal with -- one has to suppress homologous recombination
> DNA repair in pre-cancerous cells. Not impossible mind you but
> pretty darn difficult.
Wrong. The key point is that just swapping bits of DNA between
telomeres can do very little to stave off cell senescence and/or
death (always death in the case of cancer cells because they have
already overcome the senescence response in order to reach crisis
in the first place), because all it does is ensure that one short
telomere doesn't trigger death prematurely. For indefinite (or
even much extended) cell division you need DNA replication. DNA
repair involves a tiny bit of replication, but only a tiny bit.
> One would presumably turn down the ability to do homologous
> recombination repair system as the telomeres shorten. But I suspect
> there will be tissues where that has a significant negative impact
> (in terms of cell replacement capacity).
Wrong. The reason we know it's wrong is just that ALT is evidently
as hard to activate as telomerase is, even in cells like skeletal
muscle satellite cells where telomerase is fabulously well shut down.
So, even though at this point we don't know what aspects of our DNA
repair machinery are involved in ALT, we can actually be reasonably
confident that at least some of that machinery is very well turned
off in normal cells. That's not as surprising as it sounds, because
it doesn't imply anything for the activity of DNA repair generally:
the get-out is that there are many genes that have no constitutive
role, and only operate in unusual cells, e.g. in meiosis. Meiosis
is the best bet, in my view, for a process some of whose machinery
is essential for ALT.
> One of the problems is that we don't fully understand
> the degree to which telomere extension needs to be tuned
> for specific tissues based on their cell division rate.
> I suspect the optimal balance between telomere extending
> and shortening is not attained in many tissues.
All true, but irrelevant if we get WILT to work.
> On a positive note, though I can't discuss it, Juvensa may be on
> the path towards a "homologous recombination-based gene therapy"
> approach that may be workable. If that plays out in a successful
> way you will have a much greater toolbox to work with.
All true. (I know plenty about that work of course as I am on the
Juvensa scientific advisory board.)
Aubrey de Grey
This archive was generated by hypermail 2.1.5 : Mon Sep 15 2003 - 06:27:31 MDT