Lecture 8: Replicative immortality Flashcards
Hyperproliferation can lead to two things (after inducing replicative stress)
- Cellular senescence, permanent cell cycle arrest
- Cell death
3 morphological signs of replicative senescence
- Cells enlarge and flatten
-Replication ceases even in presence of growth factors - Metabolism continues
What is the problem when replicating chromosome ends ?
- Replication at telomeres is incomplete during each cell division
- Progressive erosion of telomeric DNA
Three things contained in Telomerase
- Telomerase retro-transcriptase (TERT), catalytic subunit
- Telomerase DNA (TR/TERC)
- Additional proteins
Where are hTERT promoter mutations found ?
Sub-ventricular zone (glioma precursor cells)
Is telomere shortening the cause or only a consequence of replicative senescence (2 experimental evidences) ?
Cause
- Senescence correlates with telomere shortening
- If telomerase is reintroduced, telomeres are maintained, and cells avoid senescence.
2 types of cells where TERT expressed at very low levels
- Germ cells, stem/progenitor cells of self-renewing tissues
- “immortalized” cell lines and cancer cells
1 type of cells where TERT is absent
Differentiated and cultured primary cells
Structure that telomeres create at the end of chromosomes and its utility
Lariat structure to protect chromosomes from and-to-end fusion
What do Shelterin components do ?
Shelterin complexes inhibit DNA repair enzymes to prevent chromosome end fusions
What happens after DNA damage ?
-> Binding of ATM or ATR to DNA
-> activate CHK1&2
-> Stabilize p53
-> Induce CDK inhibitor p21
-> Cell cycle pause
(plus de détails page 12)
What can be the effects of context-dependent alternative p53 outputs
Transient arrest by p21, or senescence (low p53), or apoptosis (high p53)
What facilitates permanent G1 arrest ?
Cell size overgrowth, correlating with weaker p53 activation
3 ways of regulating cell size
- Osomosis ?
- mTOR signaling
- Protein homeostasis
Consequences of 53BP1 recruitment or not
No 53BP1:
Re-entry into cell cycle without DNA repair, permanent G1 arrest
With 53BP1:
DNA repair before re-entry into cell cycle
Effect of Telomere shortening on p53
Activation
Effect of telomere loss on p53 deficient cells
Continued proliferation -> fusion of chromosomes -> anaphase bridges -> Breakage-Fusion-Bridge (BFB) cycles -> karyotypic disarray -> crisis (autophagy)
What does TERT expression after BFB induce ?
Cancer in 1 in 10^7 cells
Is hTERT always needed to maintain telomeres ?
No, Alternative Lengthening of Telomeres (ALT) in cancers and ES cells lacking telomerase activity
Two type of DNA stress that triggers a SASP
radiation therapy (X-ray) -> DNA damage
chemotherapy
What do the factors secreted by senescent cells ?
influence tumor growth
-proteases disorganizing tissue structure
-growth factors stimulating tumor growth
Which type of DNA stress triggers premature senescence ?
Strong mitogenic signaling
Oncogenes induce…
premature cellular senescence.
What is the second-most frequently mutated or repressed tumor suppressor gene ?
CDKN2A
