The paragraph below is the abstract of an article written by CM Counter. An abstract summarizes key points or
information found within the article. Scientists often use abstracts, to determine whether they wish to read an entire
article. Based on what you have learned to date, and what is in the abstract, answer the questions on the next page.
Mutat Res. 1996 Oct;366(1):45-63.
The roles of telomeres and telomerase in cell life span.
Counter CM1.
Abstract
Telomeres cap and protect the ends of chromosomes from degradation and illegitimate recombination. The termini of a
linear template cannot, however, be completely replicated by conventional DNA-dependent DNA polymerases, and thus in
the absence of a mechanisms to counter this effect, telomeres of eukaryotic cells shorten every round of DNA replication.
In humans and possibly other higher eukaryotes, telomere shortening may have been adopted to limit the life span of
somatic cells. Human somatic cells have a finite proliferative capacity and enter a viable growth arrested state called
senescence. Life span appears to be governed by cell division, not time. The regular loss of telomeric DNA could
therefore serve as a mitotic clock in the senescence programme, counting cell divisions. In most eukaryotic organisms,
however, telomere shortening can be countered by the de novo addition of telomeric repeats by the enzyme telomerase.
Cells which are "immortal' such as the human germ line or tumour cell lines, established mouse cells, yeast and ciliates,
all maintain a stable telomere length through the action of telomerase. Abolition of telomerase activity in such cells
nevertheless results in telomere shortening, a process that eventually destabilizes the ends of chromosomes, leading to
genomic instability and cell growth arrest or death. Therefore, loss of terminal DNA sequences may limit cell life span by
two mechanisms: by acting as a mitotic clock and by denuding chromosomes of protective telomeric DNA necessary for
cell viability.
http://mcb.berkeley.edu/courses/mcb135k/telomeres.html
1. What is a telomere and what purposes does a telomere have? (be specific, I want details)
2. What is chromosome degradation and illegitimate recombination
3. What is the termini of a linear template, and why are DNA polymerases unable to replication of the termini?
4. What do the phrases “ finite proliferative capacity” and “viable growth arrested state (senescence) mean?
5. What is a mitotic clock?
6. What is the role of telomerase, and how does it relate to fetal cells, somatic cells, and cancer cells
7. What advantages can we gain by learning about telomerase?
Often, additional articles must be researched to find “simpler explanations” (ie, you have no idea what the vocabulary
means. One issue, is that the vocabulary may not be exact. Read each part of the outline below, and identify what
question each section could help to answer.
Telomeres
What are they?

Ends of linear chromosomes
o Repetitive DNA sequence: TTAGGG in vertebrates
o Specialized proteins
o Form a "capped" end structure
Why are telomeres important?




Telomeres allow cells to distinguish chromosome ends from broken DNA
o If DNA is broken there are two options after the cell cycle is stopped: Repair or Death
 Repair can occur in two ways:
 Homologous Recombination (HR) -- Error-free but need homologue nearby
 Non-homologous end-joining (NHEJ) -- Error-prone but saves chromosome from
degradation
Telomeres prevent chromosome fusions by NHEJ
o Fusion-bridge-breakage cycles leads to genomic instability which in turn can result in cell death or
neoplastic transformation
Telomeres are specialized structures that are essential for protecting chromosome ends and ensuring
chromosome stability
Telomeres also provide a mechanism for "counting" cell divisions
Telomere shortening - the end replication problem



Telomeres shorten with each cell division (S phase)
o The "end replication" problem:
 DNA replication is bidirectional
 DNA polymerases are unidirectional
 DNA polymerases must initiate replication from a primer
o Therefore: each round of DNA replication leaves 50-200 bp DNA unreplicated at the 3' end
Cells with telomeres that are 10-12 kb in length (average) divide 50-60 times
Cellular senescence is triggered when telomeres are on average 4-6 kb
How do immortal cells avoid telomere loss (i.e. solve the end replication problem)?
Telomerase = the key to replicative immortality

Enzyme (reverse transcriptase) with protein + RNA subunits
o Adds telomeric repeats directly to 3' overhang (uses its own RNA component as a template)
1. Vertebrate telomere repeat: TTAGGG
2. Vertebrate telomerase RNA template: AATCCC
o Overcomes telomere shortening/end replication problem
1. Added back to somatic cells
 Prevemts telomere shortening
 Prevents replicative senescence
2. However cells that express telomerase still undergo cellular senescence in response to DNA
damage, oncogenes, etc.




Expressed by germ cells and early embryonic cells
NOT expressed by most somatic cells (human)
Expressed by certain stem cells, but highly regulated
Expressed by 80-90% of tumor cells!
o remaining 10-20% still need to overcome end replication problem -- do so by alternative telomere
lengthening mechanism (ALT), probably recombination
Telomere Hypothesis of Aging


Hypothesis: Telomeres shorten with age (T cells, tissue with high cell turnover)
o Therefore, telomere shortening is a cause of aging
What is wrong with this hypothesis?
o Telomere contributes to aging ONLY IF replicative senescence contributes to aging
 Therefore, telomerase will prevent aging and/or restore youthfulness
o Telomerase protects against replicative, but not other forms of cellular senescence
Telomerase: Useful for expanding cells for medical use
Telomerase Inhibitors: Useful for inhibiting or killing tumor cells
This is the summary of the above article.
You would have missed quite a bit, if you had only read the summary. How often do we do this???
Summary




Telomeres are essential for chromosome stability
Telomere shortening causes replicative senescence. Other inducers of cellular senescence are telomere independent
Telomerase prevents telomere shortening and replicative senescence
The telomere hypothesis of aging hinges on the cellular/replicative senescence hypothesis of aging
Finally read the article on Facts about telomeres and telomerase.
What makes this article different from the abstract and the outline.
Finally, go back to the original abstract. If you have answered all the questions correctly, and read the outline and the
article, you should be able to make sense of the abstract.
You CAN read scientific articles…but “stepping up” to the article is important. Learning must be done in steps..so
simply reading an abstract or a summary may not be enough to get the information you need, but it could be enough
to pique your interest!