In: Biology
What are telomeres, and explain how telomerase prevents the shortening of the linear chromosome. Use illustrations if needed.
Telomere and Telomerase
i. The replication always takes place from 5′ to 3′
direction in the new strand. The DNA polymerase enzyme is not able
to synthesize the new strand at the 5′ end of the new strand. In
other words, a small portion (about 300 nucleotides) in the 3′ ends
of the parent strands could not be replicated.
ii. This end piece of the chromosome is called telomere. Therefore
another enzyme, telomere terminal transferase or telomerase takes
up this job of replication of the end piece of chromosomes. The
telomeres are noncoding repetitive sequences.
iii. After the normal replication, there is only single strand in
this region; so this portion is degraded by exonucleases. This
broken end leads to aberrant recombinations or end to end fusions.
Unless there is some mechanism to replicate telomeres, the length
of the chromosomes will go on reducing at each cell division. The
stability of the chromosome is thus lost. Many genes might also be
lost in the process.
iv. The shortening of telomere end is prevented by an enzyme
telomere terminal transferase or telomerase. It contains an RNA
component, which provides the template for telomeric repeat
synthesis.
v. Telomerase acts like a reverse transcriptase. Telomerase
recognizes 3′ end of telomere, and then a small DNA
strand is synthesized.
Telomerase: This complex contains a protein (Tert) that acts as a reverse transcriptase and a short piece of RNA (Terc) that acts as a template. The CA-rich RNA template base-pairs with the GT-rich, single-stranded 3 -end of telomeric DNA. The reverse transcriptase uses the RNA template to synthesize DNA in the usual 5 →3 direction, extending the already longer 3 -end. Telomerase then translocates to the newly synthesized end, and the process is repeated. Once the GT-rich strand has been lengthened, primase activity of DNA pol α can use it as a template to synthesize an RNA primer. The RNA primer is extended by DNA pol α, and then removed.
vi. Terminal restriction fragments from 70-year old donors are
shorter than those from 20-year-old ones. Thus, in old age, the
telomerase activity is lost; leading to chromosome instability and
cell death.
vii. As a general rule, cancer cells have continued presence of
telomerase, and the chromosome length equilibrium is maintained,
leading to continued cell division. As cancer cells have increased
and persistent activity of telomerase, the cancer cells become
immortal. Telomerase is also implicated in other human diseases
like diabetes, aplastic anemia, Bloom’s syndrome, Fanconi’s anemia
and Ataxia telangiectasia. Elizabeth Blackburn, Carol Greider and
Jack Szostak discovered the telomeres and telomerase, all the three
were awarded Nobel prize in 2009.
viii. Telomerase is a therapeutic target for cancer chemotherapy.
Inhibition of telomerase can effectively control the multiplication
of malignant cells. The use of antisense oligonucleotides against
the RNA component of the telomerase arrests uncontrolled cell
proliferation with minimum side effects.