21st Feb - Senescence Flashcards

1
Q

What is cellular senescence?

A

A terminal differentiation state in which metabolically active cells are permanently and irreversibly arrested with distinct morphological changes

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2
Q

What is the hayflick limit?

A

Normal human cells will divide a set number of times before they stop permanently

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3
Q

What is telomere shortening?

A

With each division telomeres shorten because duplication is not entirely complete

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4
Q

What are telomeres?

A

repetitive DNA sequences (TTAGGG) that cap the chromosomes and protect their ends from erosion

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5
Q

What is the end replication problem?

A

The inability of DNAP to work on 3’ ends leading to telomere shortening

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6
Q

How does telomere shortening cause cell cycle arrest?

A

When the telomeres become too short (<12.8 repeats of repetitive clusters) it leads to cell cycle arrest, senescence and apoptosis

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7
Q

What is the function of telomerase?

A

It can elongate the telomeres, refreshing the cell

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8
Q

What is SIPS?

A

Stress induced premature senescence

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9
Q

What triggers SIPS?

A

Detection of DNA damage signals

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10
Q

What are the main pathways for the activation of senescence?

A

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

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11
Q

What are the markers of senescence?

A
Growth Arrest
SA-Bgal
DNA Damage Foci
Heterochromatin foci
p16INK4A
Senescence associated secretory phenotype
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12
Q

How does senescence associated-Beta galactosidase show senescence?

A

Hydrolase enzyme that catalyzes the hydrolysis of β-galactosides into monosaccharides only in senescent cells, thus turning senescent cells blue

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13
Q

How are DNA damage foci created?

A

DNA damage response proteins (e.g. ATM) accumulate in the vicinity of a chromosomal ds DNA break creating subnuclear foci

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14
Q

What are heterochromatin foci?

A

Specialized domains of facultative heterochromatin that contribute to silencing of proliferation promoting genes e.g. E2AF

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15
Q

How can heterochromatin foci be visualized?

A

immunoflouresence staining

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16
Q

What are the characteristic chromatin marks associated with heterochromatin foci?

A
H3K9me3
H4K20me3
macroH2A
gamma-H2AX
HP1
Hypo-acetylation
DNA methylation
17
Q

What form of cancer is p16INK4a used as a marker for?

A

Cervical cancer

18
Q

Give some examples of molecules that senescent cells secrete to the environment

A
Promote senescence
IGFBPs
ILs
PAI1
IFNs
TGFbata

Inhibit senescence
IGFs
WNT2

19
Q

Give an example of a human tumour showing cell senescence and their oncogenic event

A

Dermal neurofibromas –NF1 inactivation

Nevi – BRAFv600E mutation

20
Q

Describe an experiment performed to test whether ageing was linked to cancer suppression and its conclusion

A

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

21
Q

Describe the SASP

A

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

22
Q

What is antagonistic pleiotropy?

A

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

23
Q

Outline an experiment which delayed ageing by Baker (2011)

A

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