Cell Senescence and Cancer

Question 1

What is cell senescence?

Answer 1

• a form of permanent arrest of cell proliferation
• major defence against cancer
• contributes to mechanisms of ageing

Question 2

When is cell senescence activated?

Answer 2

1. Extended proliferation - replicative senescence
2. Activation of an oncogene - oncogene-induced senescence (OIC)
3. Other genotoxic (DNA damaging stresses

Question 3

What are molecular properties/markers of senescent cells?

Answer 3

• expression of effectors (cell cycle inhibitors) eg p16, p53
• DNA damage signalling
• increased lysosomal content

Question 4

What is SASP?

Answer 4

• “senescence associated secretory phenotype”
• senescent sells secrete many inflammatory factors:
  1. Cytokines and their receptors (IL6, IL8 etc)
  2. Proteases (MMPs)
  3. Angiogenic factors (VEGF)
  4. Other growth factor (IGF2 etc)

Question 5

What is the DNA end replication problem?

Answer 5

• the section of DNA at the 3’ end of each strand can’t be replicated by DNA polymerase
• therefore a small stretch of DNA at the 3’ end can’t be replicated normally

Question 6

How do telomeres solve the DNA end replication problem?q

Answer 6

• telomeres are DNA structures at the ends of chromosomes
• made of repeats of DNA hexamer TTAGGG
• enzyme telomerase (protein RNA complex) can replicate telomeric DNA in 5-phase by reverse transcribing the DNA hexamer from its own RNA sequence
• it joins these onto the 3’ end to allow the strand to maintain its length
• telomerase activity is highest in germ cells

Question 7

What are the 2 main subunits of telomerase?

Answer 7

1. TERT = telomerase reverse transcriptase (protein part)
2. TERC = telomerase RNA component (RNA part)

Question 8

What happens when telomeres get too short?

Answer 8

• most somatic cells lack telomerase activity so telomeres shorten as they divide
• replicative senescence is trigged in normal cells when the telomeres get quite short so the population arrests

Question 9

How are telomeres protected?

Answer 9

• normal telomeres end in loops and bind a protective protein cap of shelterin complexes
• this cap conceals the chromosome end from DNA damage signalling and repair systems

Question 10

What happens to the cap on telomeres when they shorten?

Answer 10

• when the telomeres shorten the cap destabilises and breaks off
• the exposed end is now recognised as a DNA break which sets up stable DNA damage signalling but not repair
• p53 is recruited and activated by kinases and signals growth arrest
• DNA damage signalling (without repair) seems to be the core trigger of cell senescence

Question 11

What happens when DNA damage signalling doesn’t work?

Answer 11

• if the telomeres are too short and p53 is activated, if the senescence signalling does not work, the cells can proliferate and turn into cancer cells
• This can lead to cancer such as melanoma cancer

Question 12

What happens to mice that have cells that express p16 removed?

Answer 12

• median lifespan of mice increased by 25%
• delayed deterioration in organs including heart, kidneys, fat
• delayed tumourigenesis
• extended healthspan

Question 13

Which cells are naturally immortal?

Answer 13

• Germ line cells and embryonic/pluripotent stem cells express TERC and TERT therefore they have telomerase activity and maintain full length telomeres
• whereas most somatic cells express TERC but only a little/no TERT so telomeres shorten at division

Question 14

Do adult stem cells have telomerase?

Answer 14

• somatic/adult stem cells are stem cells still present after birth
• cells in the basal epidermis and bone marrow have some telomerase activity though not enough to make them immortal
• they still shorten but a low slower than other somatic cells so are said to gradually senescence

Question 15

Why do we need cell senescence to act as a tumour suppressor?

Answer 15

• p53 and p16 are products of the two genes most commonly defective in advanced human cancers
• cell senescence is the only established function of p16 and an important one of p53
• reactivated telomerase activity is reported in 90% of human cancer cell lines
• p16 and p53 defects and telomerase activity are required to immortalise cells
• immortalisation is a hallmark of cancer and is necessary to produce an advanced cancer

Question 16

How does cell senescence suppress cancer?

Answer 16

• normal cell proliferates due to oncogenic mutation that forms a benign tumour
• this activates cell senescence which stops the tumour from growing
• more mutations are needed to escape senescence to form a malignant tumour, but this is very rare

Question 17

What are viral oncogenes that inactive the p53 and p16/Rb pathways?

Answer 17

1. SV40 produces Large T that targets both
2. HPV produces E6 for p53 and E7 for Rb
3. Adenovirus produces E1B for p53 and E1A for Rb

Question 18

What happens when cell senescence occurs in moles?

Answer 18

• moles (naevi) typically have an activated oncogene (BRAF/NRAS)
• a mutation in one cell leads to proliferation that creates a visible mole
• the mole then arrests its growth through cell senescence to prevent melanomas
• naevi are 3000x more common that melanomas so senescence is effective

Question 19

What is telomeric crisis?

Answer 19

• if senescence is disrupted due to a deficiency in p53 and Rb (due to oncogene) the telomeres become lost
• the cells then divide and die
• or they are liable to be joined to another exposed DNA end by the DNA repair system
• this doesn’t not occur in immortal cells as they have enough telomerase activity to keep the cells alive

Question 20

How do the cells escape from crisis?

Answer 20

• some of the aberrant chromosomal patterns are lethal, some are viable
• its rare that a mutation permits telomere extension
• telomerase is able to rebuild telomeres on to the chromosome ends