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Science Forum Index » Philosophy Forum » On Telomeres
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| Frederick |
 Posted: Thu Dec 25, 2003 6:31 pm |
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MOLECULAR BIOLOGY: ON TELOMERES
ScienceWeek http://www.scienceweek.com
The following points are made by Vicki Lundblad (Nature 2003
423:926):
1) In every organism, maintaining the integrity of the genome is
a crucial endeavor. One aspect of genome maintenance involves
protecting telomeres, the natural ends of linear chromosomes.
This task is achieved by a suite of specialized protein
complexes, which are anchored to chromosome ends through their
association with further proteins that bind directly to telomeric
DNA. The resulting structure prevents events that would be
catastrophic for the genome, such as the loss of terminal DNA
sequences or end-to-end chromosome fusions.
2) One of the complexes involved in telomere maintenance is an
enzyme called "telomerase", which adds DNA back to telomeres that
have become eroded. Several other proteins also regulate this
complex. But how the different proteins talk to one another -- to
keep telomeres the right length, to protect them, and to
replicate them during cell division -- is poorly understood.
3) Telomeric DNA is composed of G-rich repeats -- reiterations of
a short DNA sequence that does not code for protein and is high
in guanine (G) nucleic-acid bases. It also has a single-stranded
stretch that overhangs the end of the double-stranded (duplex)
telomeric region. This overhang is the substrate for telomerase,
which elongates chromosome ends by adding G-rich repeats. The
importance of telomerase is evident from studies of yeast and
human cells in which reductions in telomerase levels produce a
steady decline in telomere length that eventually blocks cell
division. Not surprisingly, then, telomerase is highly active in
systems such as the blood and reproductive system, which rely on
continuous replenishment through cell proliferation(3). Much to
the interest of cancer biologists, telomerase levels are also
increased in most human tumors, providing a potential target for
the development of anticancer drugs(4).
4) In normal cells, telomerase activity is carefully controlled
by several mechanisms. For instance, subunits that are part of
the telomerase complex itself can positively regulate the enzyme,
for example by mediating recruitment of the complex to chromosome
ends(5). Surprisingly, proteins that bind to the duplex region of
the telomere can also be potent regulators, even though they do
not appear to associate physically with telomerase. These duplex-
binding proteins -- which include Rap1 in budding yeast and the
TRF1 and TRF2 proteins in human cells -- can "count" the number
of G-rich repeats and, when telomeres become overly long, inhibit
further telomerase activity. Missing from this elegant proposal
for telomere-length regulation, however, is an explanation for
how information from the duplex portion of the telomere is
relayed to the very tip of the chromosome -- the site of
telomerase action(1,2).
References (abridged):
1. Loayza, D. & de Lange, T. Nature 423, 1013-1018 (2003)
2. Colgin, L. M., Baran, K., Baumann, P., Cech, T. R. & Reddel,
R. R. Curr. Biol. 13, 942-946 (2003)
3. Lee, H.-W. et al. Nature 392, 569-574 (1998)
4. Damm, K. et al. EMBO J. 20, 6958-6968 (2001)
5. Evans, S. K. & Lundblad, V. Science 286, 117-120 (1999)
Nature http://www.nature.com/nature
--------------------------------
SENESCENCE: DOES IT ALL HAPPEN AT THE ENDS?
The following points are made by S.A. Stewart and R.A. Weinberg
(Oncogene 2002 21:627):
1) Over 60 years ago Barbara McClintock [1902-1992] described the
telomere and suggested that it protected the chromosome from
illegitimate or end-to-end fusion, thus functioning to protect
the genome. Since that time we have discovered that the telomere
is a complex structure composed of both DNA and a growing list of
associated proteins that together serve to regulate the length of
the telomere and, as predicted by McClintock, protect genomic
integrity.
2) In addition to its protective role, the telomere has also been
hypothesized to serve as a molecular clock that tallies the
number of cell divisions and limits further divisions at a
predetermined point. However, the precise role of telomeres in
predicting and limiting cellular lifespan remains a matter of
much debate.
Oncogene http://www.nature.com/onc/
--------------------------------
TELOMERASE AND SENESCENCE.
The following points are made by S. E. Artandi et al (Proc. Nat.
Acad. Sci. 2002 99:8191):
1) Telomerase, the reverse transcriptase that synthesizes
telomeric repeats, is present at low levels in human tissue stem
cells, progenitor cells, and germ cells, and is undetectable in
the vast majority of adult somatic tissues. Insufficient
telomerase activity and the inability of DNA polymerase to
replicate the extreme ends of chromosomes lead to telomere
attrition with each round of cell division in the setting of
organ renewal with advancing age (1), high-turnover disease
states (2), and passage in culture (3). During human
tumorigenesis, telomerase becomes reactivated by transcriptional
up-regulation of TERT, the catalytic subunit of telomerase (4).
One critical function served by TERT reactivation during cancer
progression is to avert the adverse consequences of telomere
shortening and loss of chromosomal capping function (5). Less
clear, however, is whether the pro-oncogenic activity of
telomerase extends beyond its role in maintaining telomere
function.
2) In human cells, progressive shortening of telomeres
precipitates replicative senescence after 60-80 divisions of
primary human fibroblasts (3) and crisis after extended division
of cells expressing viral oncoproteins. Introduction of
telomerase into primary human cells stabilizes telomeres,
prevents both senescence and crisis, and endows cells with
unlimited proliferative potential. The ability of telomerase to
rescue cells from the adverse consequences of telomere
dysfunction is likely critical for its role in facilitating
malignant transformation of primary human cells and in
maintaining the viability of established cancer cells.
3) In summary: Telomerase is up-regulated in the vast majority of
human cancers and serves to halt the progressive telomere
shortening that ultimately blocks would-be cancer cells from
achieving a full malignant phenotype. In contrast to humans, the
laboratory mouse possesses long telomeres and, even in early
generation telomerase-deficient mice, the level of telomere
reserve is sufficient to avert telomere-based checkpoint
responses and to permit full malignant progression. These
features in the mouse provide an opportunity to determine whether
enforced high-level telomerase activity can serve functions that
extend beyond its ability to sustain telomere length and
function. The authors report the generation and characterization
of transgenic mice that express the catalytic subunit of
telomerase (mTERT) at high levels in a broad variety of tissues.
Expression of mTERT conferred increased telomerase enzymatic
activity in several tissues, including mammary gland,
splenocytes, and cultured mouse embryonic fibroblasts. In mouse
embryonic fibroblasts, mTERT overexpression extended telomere
lengths but did not prevent culture-induced replicative arrest,
thus reinforcing the view that this phenomenon is not related to
occult telomere shortening. Robust telomerase activity, however,
was associated with the spontaneous development of mammary
intraepithelial neoplasia and invasive mammary carcinomas in a
significant proportion of aged females. The authors suggest these
data indicate that enforced mTERT expression can promote the
development of spontaneous cancers even in the setting of ample
telomere reserve.
References (abridged):
1. Hastie, N. D., Dempster, M., Dunlop, M. G., Thompson, A.
M., Green, D. K. & Allshire, R. C. (1990) Nature (London) 346,
866-868.
2. Rudolph, K. L., Chang, S., Millard, M., Schreiber-Agus, N.
& DePinho, R. A. (2000) Science 287, 1253-1258.
3. Harley, C. B., Futcher, A. B. & Greider, C. W. (1990) Nature
(London) 345, 458-460.
4. Kim, N. W., Piatyszek, M. A., Prowse, K. R., Harley, C.
B., West, M. D., Ho, P. L., Coviello, G. M., Wright, W. E.,
Weinrich, S. L. & Shay, J. W. (1994) Science 266, 2011-2015.
5. Blackburn, E. H. (2000) Nature (London) 408, 53-56.
Proc. Nat. Acad. Sci. http://www.pnas.org
ScienceWeek http://www.scienceweek.com
--
Best,
Frederick Martin McNeill
Poway, California, United States of America
mmcneill@fuzzysys.com
http://www.fuzzysys.com
http://members.cox.net/fmmcneill/
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Phrase of the week :
"There is no doubt that great revolutions of human scientific
thought will occur in the next century, and in the century after
that, and in thousands of centuries afterward. So which of our
current pet scientific dogmas will be among the first washed away
by new facts and sudden clarities?" -- Anonymous
 )))Snort!)
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