P.J.Chapman at durham.ac.uk
Mon Mar 16 15:50:32 EST 1998
On Tue, 10 Mar 1998, smc wrote:
> On Mon, 09 Mar 1998 22:04:33 -0600, Iuval Clejan <spring at jumpnet.com> wrote:
> Regarding C. elegans, I'm pretty certain all its cells are post-mitotic
> and so are not replaced. However, CE still ages and dies, as do all
> post-mitotic cells (e.g. neurons), and so this is where the involvement
> of telomeres and telomerase in ageing becomes uncertain. My best bet is
> that telomeres are simply an anti-cancer mechanism inhibiting the number
> of times a cell can replicate, especially since the telomers of humans
> who have died of old age are still quite long and go on dividing in
> vitro (albeit fewer times than a young person).
You might be interested to look at some of the recent evidence published
on SGS1 in yeast - a RecQ-like subfamily DNA helicase which is related to
the Werner Syndrome gene product in humans. Although it is difficult to
shrink this down into a concise summary I will try.
SGS1- cells exhibit accelerated ageing. This is suggested by three pieces
1. They have a shortened lifespan.
2. They become sterile more quickly than wild type cells.
3. Their nuceoli fragment, due to the accumulation of rDNA circles (more
later), more quickly than wild type cells.
It is this accumulation of rDNA circles which is the researchers think is
the cause of ageing, at least in yeast. Extrachromosomal rDNA circles
(ERCs) are formed by excessive homologous recombination. It is thought
that the SGS1 gene product repressed the formation of these, although
exactly how it does it is unknown.
How does this relate to the telomeres? The Sir silencing complex is a
protein complex which is localised to the telomeres. In wild type cells,
it is redistributed from the telomeres to the nucleolus as the cell ages.
This is thought to extend lifespan, as cells deficient in the Sir
silencing complex have a shorter lifespan than wild type cells (note that
this is not the same as accelerated ageing).
The authors suggest that the Sir silencing complex is present primarily to
stabilise the telomeres. However, when the nucleolus starts to fragment
(due to ERC formation), it is relocalised from the telomers to help
stabilise the nucleolus. This 'last ditch' measure help to extend
the lifespan of the cell line by slowing ERC formation.
In SGS1- cells, however, the Sir complex relocalises to the nucleolus
earlier than in wild type cells. This is in association with the
increased ERC formation. So maybe a threshold amount of nucleolar
fragmentation is reached earlier than in wild type cells, causing the Sir
complex to be relocalised earlier too.
This point is where the facts stop and my own hypotheses kick in.
Having removed the Sir complex from the telomeres, the effect on them must
be to destabilise them. Thus they shorten. So, is telomere shortening
what CAUSES ageing, or is telomer shortneing CAUSED BY ageing (via the ERC
formation/nucleolar fragmentation idea).
Recently it has been shown that expressing telomerase in human cells
causes them to become immortal. The authors of this paper suggest that
this is by preventing telomere shortening. However, I hope that you can
see from my previous argument that telomerase could just as easily be
acting by stabilising the nucleolus instead, seeing as both the telomeres
and the nucleolus are stabilised by the Sir complex suggesting a similar
In my opinion, the idea of nucelolar fragmentation causing ageing seems
more likely than the idea of telomere shortening. This is for several
1. The nucleolus containes 'unpacked' DNA - that part of the genome being
actively transcribed. The telomeres are simply repeating bits of DNA
acting as padding at the end of the chromosomes. Surely this makes the
nucleolus more important to the cell?
2. The very fact that the Sir complex is removed from the telomeres to
the nucleolus also suggests the importance of stabilising the nucleolus.
If the telomeres were so important, why move the Sir complex?
Sorry to have prattled on for so long but, as I said, this is quite a
complex subject. However, I thought it needed mentioning because with all
the hype over telomere shorteing and ageing, people seem to havbe
forgotten that there may be alternative ideas.
If your interest has been raised by what I've written, read the article in
Cell entitled 'rDNA Circles - A cause of ageing in yeast?'. I can't
remember the exact reference but it should be pretty easy to find.
I look forward to some interesting discussion on this point.
(University Of Durham, UK)
PS. Note that although I have been talking about cell immortality, I
really mean cell LINE immortality. Sorry.
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