MBB 267 Week 4: Barnes 8 Flashcards
what is a telomere?
A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes, with a 3’ overhang
What is the problem that telomeres solve?
Lagging strand of DNA replication requires an RNA primer, which is later removed
a. And the gap is filled in from the adjacent Okazaki fragment
b. But this is not possible at the end of a linear chromosome
What is the sequence for telomeres in mammals?
All mammals: TTAGGG
a. 10-15 kb in human
How does the cell protect chromosomes ends from being repaired?
By the shelterin complex:
a. A number of specialised proteins bind telomere DNA, and each other, including TRF1, TRF2, and POT1 in humans
b. These form a “cap” on the telomere to:
c. differentiate it from DNA breaks
d. promote the formation of a special tertiary structure in the DNA called a t-loop
e. recruit telomerase
f. protect from nucleases
When is telomerase activated?
Activated once telomere length falls below a threshold
How does telomerase work?
RNA component base-pairs with the 3’ overhang
a. Elongation of the overhang using RNA as a template
b. Telomerase translocates further out along the 3’ overhang
c. Elongation of the overhang using RNA as a template
d. RNA is removed, synthesis of the second strand by DNA polymerase using the overhang as a template
What factors effect the telomerase activity in cells?
Single cell eukaryotes: “immortal” – high telomerase activity
a. Humans:
i. High telomerase activity in stem cells and germline cells
ii. Low or undetectable telomerase activity in somatic cells
iii. In general, telomeres in somatic cells shorten as the organism grows older. (in humans, 50-200 bp per cell division)
iv. Telomeres shorter than a certain length are too short to bind shelterin. This triggers cell cycle arrest, senescence, apoptosis, and genome instability
What is the relationship between telomerase and ageing?
oxidative stress can speed up telomere shortening (build-up of single- strand breaks)
a. Shorter telomeres tend to correlate with ageing-related disease
What is the relationship between telomerase and cancer?
Elevated telomerase activity in 90% of cancer cells (alongside other mutations)–allows them to become “immortal”
a. Often due to mutations in the promoter for the protein portion of telomerase
b. Telomeres and telomerase are therefore a good drug target
c. By interfering with telomerase expression or stabilising structures in the telomere DNA, preventing it from being replicated
