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Flashcards in Telomeres Deck (11)
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1
Q

What are the functions of telomeres and what would happen if they weren’t there?

A

Protection from replication problms and a tumour supressor.

Without telomeres a cycle of fusion, anaphase bridges, breakage and then fusion again occurring in a loop leading to mutations and chromosome instability.

2
Q

What is the structure of telomeres?

A

Conserved structure of a tandem repeat of TTAGGG. The G rich strand is orientated 5’-3’ and ends with a single strand overhand. Length between and within species varies wildly due to environment, genetics and end replication problem.

3
Q

What is the end replication problem?

Will be required to draw a diagram of it so get learning!

A

As the 3’ strand is replicated many primers anneal and form okazaki fragments. At the end the primer doesn’t perfect fit leaving an overhang that can’t be replicated., as well as this the overhang must be extended for telomere function.

4
Q

What lengthens telomeres?

A

Telomerase complex. First discovered in tetrahymena. Complex includes TERT - a reverse transcriptase and TERC - RNA component as well as many other proteins.

TERC anneals to the 3’ overhang and TERT fills in the gap, then the whole complex moves up one repeat (translocates) and the process continues. The 5’ strand is elongated via a protein complex called CST.

5
Q

How is telomerase regulated?

A

Mutation of TERC prevent RNA binding or changes what the repeat sequence will be. The secondary structure of TERC is conserved and expressed in almost all cells. TERT expression is regulated to germline and stem cells.

Other proteins binds to TERC such as DKC1 and these modify the RNA component (DKC disease maybe).Many of these are snoRNPs - small nucleoolar ribonucleoproteins.

6
Q

What is the structure of nucleosomes of telomeres?

A

Telomeric chromatin contains heterochromatic modifications. Never the less telomeric DNA is transcribed into TERRA creating G rich sequences - probably involved in setting up chromatin modifications.

7
Q

What happens at the end of telomeres?

A

Shelterin complexes bind on top of nucleosomes and result in the T and D loops structure being formed. Shelterin complex made up of 6 proteins, 4 are 10x more abundant that the other 2.

TRF1 and TRF2 are 2 of the core proteins which binds double stranded repeats they are essential form capping and without them the cell cycle arrests. TIN2 stabilises TRF1 and TRF2. the 2 non core proteins are POT1 and TPP1 and form the lynch pin of the shelterin complex.

Shelterin complex protects the telomere from DNA damage DSB repair mechanisms. TRF2 and POT1 repress the ATM and ATR response respectively which would normally cause fusion.

8
Q

What is the hayflicklimit.

A

Leonard hayflick noticed cells could only replicate a certain number of times. They then entered senescence. He predicted a counting mechanism. This mechanism if telomeres. TL decreases with age and is much faster at a younger age.

When TL is short enough it trigger cellular senescence. If this point is passed by overcoming cell checkpoints then TL continues to decrease until it reaches crisis point and the cell apoptoses.

9
Q

How does TL effect mice and humans?

A

TERT -/- mice are normal for a while but eventually show chromosome rearrangement, decreased size and neural tube defects. Eventually get premature ageing.

Decreased TL increases risk of age related disease. DKC results in progressive bone marrow insufficiency and genetic anticipation. Dominant inheritance suggests haplo insufficiency. IPF have mutations in TERT and TERC.

10
Q

How does telomere length effect cancer risk?

A

Long vs Short
Evidence for both
Studies probably have reverse causation and survivor effect resulting in positive result for short TL
Recent MR study suggested only long TL for cancer.

11
Q

90% of cancers have activated telomerase - what do the other 10% have?

A

ALT - recombination like process, requiring MRN protein complex. Very chaotic process with alot of genomic instability. Required HR but still need to block NHEJ