21st Feb - Senescence Flashcards
What is cellular senescence?
A terminal differentiation state in which metabolically active cells are permanently and irreversibly arrested with distinct morphological changes
What is the hayflick limit?
Normal human cells will divide a set number of times before they stop permanently
What is telomere shortening?
With each division telomeres shorten because duplication is not entirely complete
What are telomeres?
repetitive DNA sequences (TTAGGG) that cap the chromosomes and protect their ends from erosion
What is the end replication problem?
The inability of DNAP to work on 3’ ends leading to telomere shortening
How does telomere shortening cause cell cycle arrest?
When the telomeres become too short (<12.8 repeats of repetitive clusters) it leads to cell cycle arrest, senescence and apoptosis
What is the function of telomerase?
It can elongate the telomeres, refreshing the cell
What is SIPS?
Stress induced premature senescence
What triggers SIPS?
Detection of DNA damage signals
What are the main pathways for the activation of senescence?
Senescence signals –> p16 –| CDKs –| RB –| E2F –> senescence
Senescence signals –> p16 –| CDKs –| RB –> senescence
Senescence signals –> ARF –| HDM2 –| p53 –> p21 -> senescence
Senescence signals –> p53 –> p21 –> senescence
What are the markers of senescence?
Growth Arrest SA-Bgal DNA Damage Foci Heterochromatin foci p16INK4A Senescence associated secretory phenotype
How does senescence associated-Beta galactosidase show senescence?
Hydrolase enzyme that catalyzes the hydrolysis of β-galactosides into monosaccharides only in senescent cells, thus turning senescent cells blue
How are DNA damage foci created?
DNA damage response proteins (e.g. ATM) accumulate in the vicinity of a chromosomal ds DNA break creating subnuclear foci
What are heterochromatin foci?
Specialized domains of facultative heterochromatin that contribute to silencing of proliferation promoting genes e.g. E2AF
How can heterochromatin foci be visualized?
immunoflouresence staining
What are the characteristic chromatin marks associated with heterochromatin foci?
H3K9me3 H4K20me3 macroH2A gamma-H2AX HP1 Hypo-acetylation DNA methylation
What form of cancer is p16INK4a used as a marker for?
Cervical cancer
Give some examples of molecules that senescent cells secrete to the environment
Promote senescence IGFBPs ILs PAI1 IFNs TGFbata
Inhibit senescence
IGFs
WNT2
Give an example of a human tumour showing cell senescence and their oncogenic event
Dermal neurofibromas –NF1 inactivation
Nevi – BRAFv600E mutation
Describe an experiment performed to test whether ageing was linked to cancer suppression and its conclusion
Test by KO studies
p53 -/- = lethal
p53 OE - expected accelerated ageing but received mixed results, super p53 led to cancer protection but normal ageing therefore indicates the two can be seperated, hypomorphic MDM2 knock in elevated p53 and led to normal ageing and cancer prevention, p53 and ARF knock in had an anti-ageing effect and prevented cancer, suggeting the two are linked
–> The relationship between cancer and ageing is still unclear
Describe the SASP
The senescence associated secretory phenotype
Is an autocrine method of regulating senescence acting as a positive feedback loop, secreted from the senescent cell. It is not required for senescence to occur
What is antagonistic pleiotropy?
SASP is believed to have a paracrine function causing neighbouring cells to transform into proinflammatory cells.
As in early life senescent cells are cleared away quickly –> no effect
In later life senescent cells aren’t cleared –> inflammation –> to more senescence
thus don’t need many cells ina tissue to affect it
this could explain why senescence only has tumour suppressive effects in youth
Outline an experiment which delayed ageing by Baker (2011)
Crossed drug sensitive mouse with BubRI insufficient mouse (premature ageing phenotype)
–> Hybrid offspring in which senescent cells were cleared from the mouse therefore delayed ageing, cleared p16INK4a expressing cells
