house at athena.mit.edu (Daniel J Housman) writes:
> In reading an article in the New York Times today I learned about
>telomeric shrinkage which may be the basis for some new anti-cancer drugs.
>I found this particular article interesting because it deals with a possible
>mechanism that may explain some of the molecular basis for aging.
> Apparently there is a code at the end of the telomere, a repeat
>sequence which shortens with each passing cell division. The telomere is
>the tip of the chromosome and was referred to as a metaphor to bookends.
>Gene increase has been precedented in growth of a gene such as myotonic
>dystrophy or fragile x until the gene becomes pathogenic and then amplfies
>in pathogenicity during following generations. If it is possible for a gene
>growth of a repeat sequence to be pathogenic then it may be possible for a
>repeat sequence shrinkage to be pathogenic as well. When the telomere shrinks
>below a certain size it is found that in metaphase the chromosomes stick to
>each other as they are less tightly bound in their chromosomal matrix. This
>stickyness causes the chromosomes to get caught on each other and probably
>cause severe mutations in cells that divide too many times.
> Certain cells such as non-organismal cells like amoebas and their kind,
>as well as mamalian germ cell lines have a gene expressed which protects it
>from the telomeric shaving from one generation to the next. This gene is called
>telmerase. This may explain why germ cell lines do not exhibit the symptoms
>that have been attributed to DNA damage and have been previously explained by
>some sort of super repair mechanism in the germ cells. The clock so to speak
>is genetic and so is a good candidate since radiation causes mutations like
>deletions and especially during metaphase. I refer to this because radiation
>is one of the forms in which we see a definite mimicking of major portions of
>the aging process. If radiation causes mimicked aging then it ought to be a
>genetic clock of some sort. Besides we already know that DNA is getting credit
>for everything but the kitchen sink in biology today and is a good contender
>for the aging regulator crown as has been dicussed in discussions about repair
>and other things.
Just to clear up a couple of errors. First, don't confuse
telomeres and centromeres (your title was centromeres). They are
entirely different beasts. Second, _all_ eukaryotic cells
possess telomerase (and please don't imply that amoebas aren't
organisms, they're very sensitive about that :-). Without it all chromosomes
would shrink. Also, as mentioned in your post, telomeres serve to "cap"
chromosomes -- non-telomeric ends are very sticky and tend to glue together.
One of Barbara McClintock's many great contributions was to show that
naked chromosome ends initiate a devastating cycle of chromosome joining
(of two naked ends) followed by breakage (because the resultant chromosome
has two centromeres, and gets pulled like taffy during each cell division),
resulting in two new ends for restarting the process.
The basic problem is that all known DNA-dependent DNA polymerases
can only work in one direction (5'-->3') and can only extend an existing
strand, not initiate a new one. Hence, the ends of DNA present a replication
problem.
Telomerase is apparently a specialized reverse transcriptase which
carries with it a short RNA template. This template is used to synthesize new
ends, and thus telomeres consist of repeats of these sequences.
Elizabeth Blackburn has published at least one paper claiming
that interfering with telomere production causes aging in a
cilliate system (and another in yeast???). A quick look in MedLine or
Biological Abstracts should point you to it (or in the annual index
to Nature, where it was published).
> I don't have a vast knowledge of these telomeric shrinkages and would
>request that anyone researching them produce a list of sources for my help in
>looking into this possibility. There are plenty of experiments that could be
>done to test hypotheses that include telomeres as the agent of aging since the
>length of the repeats on the ends of chromosomes are readily measurable. Also
>of note is that Huntington's disease, an elusive gene hiding on the tip of
>chromosome four, is near to the telomere and is expressed as a disease late in
>life.
While the HD locus is near the telomere, it is sufficiently distant from
it this location is believed to be irrelevant to the disease.
Aging though is complex and I wouldn't expect more than senescence to be
>covered by a theory like this, but I leave you all with the telomeres to
>munch over if you ever get finished talking about science fiction and
>medicaid.
Thank you for getting this group back where it belongs!
>Dan Housman
>MIT '95
>
Keith Robison
Harvard University
Program in Biochemistry, Molecular, Cellular, and Developmental Biology
robison at ribo.harvard.edu
