Telomeres and Telomerase Flashcards
What do telomeres do?
cap eukaryotic chromosomes at each end to maintain integrity and stability
What part of DNA are telomeres associated with?
the non-coding part
What do telomeres prevent chromosomes from doing?
fusing with each other to produce abnormal chromosomes
What happens in telomere restriction fragment analysis?
genomic DNA samples (specifically metaphase chromosomes) are digested with restriction enzymes, leaving behind telomere DNA repeats and some sub-telomeric DNA
What is telomerase?
a large ribo-nucleoprotein that includes an RNA template and a catalytic protein component; essentially a reverse transcriptase
What is a reverse transcriptase?
a DNA polymerase that synthesises DNA using an RNA template
Where is telomerase present and when it is activated?
present in G1 but activated in S phase
What does telomerase do?
recognise the tip of an existing telomere repeat sequence and the catalytic subunit elongates it in the 5’ to 3’ direction with strings of TTAGGG repeats in the absence of a complementary DNA strand, using its RNA component as the template to synthesis a new copy of the repeat
Why do somatic cells experience telomere shortening with each cell division?
they do not express telomerase
What are uncapped chromosomes sensitive to?
degradation and fusion
How are terminal sequences arranged in telomeres?
a linear pattern
What do shelterin complexes do?
protect the ends of chromosomes and maintain and regulate telomere length
What does the end replication problem hypothesise?
the ends of linear DNA cannot be replicated completely during lagging strand DNA synthesis; the removal of the RNA primer creates a gap and the strand becomes shorter with every successive round of DNA replication
Give examples of cells that proliferate and express telomerase
- stem cells
- cancer cells
- intestinal epithelial cells
- bone marrow
What does the telomere hypothesis of ageing propose?
sufficient telomere loss on one or more chromosomes in normal somatic cells triggers cell senescence, whereas reactivation of the enzyme is necessary for cell immortalisation
What is the evidence for the telomere hypothesis of ageing?
- progressive telomere shortening in normal cells from young individuals frown in culture
- shorter telomeres in colonic mucosa and blood than in foetal tissue and sperm
- telomeres are shorter in most somatic tissues from older individuals
- cell strains with shorter telomeres underwent fewer divisions in vitro
- progeria children have short telomeres compared to age-match controls
What happens when there is abundant telomerase?
addition and shorting stay balances and cells keep dividing which can lead to most human cancers
What happens when there is insufficient telomerase?
cell division stops after a delay and senescence kicks in as well as cell malfunctions and genomic instability
What happened in telomerase KO mice?
they survived for 6 generations because mice have longer telomeres to begin with
How can longevity be calculated?
if the initial length of the telomere is known
Why were chromosome fusions observed in later generations of telomerase KO mice?
due to the absence of telomeres at one end of the chromosome (Robertsonian-like configuration)
What was observed in telomerase KO mice?
- age-dependent telomerase shortening and associated chromosomal instability
- shortened lifespan and specific skin defects
- decreased body weight and reduced capacity to respond to stress
- increased spontaneous malignancies
Give examples of genetic disorders related to telomeres
- Hutchison-Gilford progeria
- Ataxia telangiectasia
- Werner’s syndrome
- Down’s syndrome
What proportion of fibroblasts can bypass senescence by telomerase?
1 in 10 million
