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Flashcards in Introduction to tumour suppressor genes Deck (23)
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1
Q

Define tumour suppressor genes (TSG)

A

TSG encodes proteins that maintain the checkpoints and control genome stability. inhibit replication and proliferation of damaged cells by :

  • repair of DNA damage (BRCA1/2)
  • apoptosis (TP53)
2
Q

What was the first TSG discovered

A
  • RB1 - 1986 (retinoblastoma)
3
Q

What is the two-hit hypothesis?

A
  • development of retinoblastoma requires two mutations, which are now known to correspond to the loss of both of the functional copies of the tumour susceptibility gene
4
Q

Explain TSG inactivation

A
  • most loss of function mutations that occur in TSG re recessive in nature - one normal allele is sufficient for the cellular control
5
Q

Describe loss of heterozygosity

A
  • additional loss of the normal functional allele
  • ‘second hit’
  • allele imbalance by which are heterozygous somatic cell becomes homozygous bc one of the 2 alleles is lost
  • this form of chromosome instability is sufficient to provide selective growth advantage and has been recognised as a major cause of tumourigenesis
6
Q

What are the functions of TSG?

A
  • oncogene antagonists
  • block proliferation (cell cycle inhibitors)
  • DNA repair
  • induce apoptosis
7
Q

DNA repair genes

A
  • endode DNA repair enzymes
  • continuously monitoring the screening chromosomes and DNA to detect damaged nucleotides
  • damage is often consequence of environmental agents
  • DNA repair enzymes detect and repair errors - can be ds breaks - caused by ionising radiation
  • single strand breaks caused. by exposure to x-rays
  • ds breaks are repaired by homologous recombination or non-homologous end joining
  • single strand breaks are repaired by base excision repair (BER) systems
8
Q

What happens if there are defects in DNA repair genes?

A
  • knockout of the DNA repair function of one or more DNA repair gene leads to sequential acquisition of more mutations
  • defects in DNA repair genes cause genomic instability and accelerate the activation of oncogenes and the loss of tumour suppressors
  • tumour arising in patients as a result of inherited defects in DNA repair genes tend to have a high mutational load.
9
Q

Describe BRCA1 + 2

A
  • repair DNA double strand breaks by homologous recombination
10
Q

Describe PARP

A
  • poly-ADP ribose polymerase

- proteins in charge of fixing single strand breaks (BER)

11
Q

Define synthetic lethality

A
  • blocking the function of PARP proteins which leads to BRCA mutated cell death
12
Q

Why are PARP inhibitors used as targeted therapy?

A
  • function to treat cancer carrying BRCA1/2 mutations
  • block catalytic action of single strand break repair function of PARP1 - leads to accumulation of ss breaks in those cells = accumulation of ds breaks
  • BRCA1/2 can’t repair ds breaks as mutated = death of BRCA1/2 cells
13
Q

List some PARP inhibitors

A
  • olaparib
  • rucaparib
  • nireaparib
  • talazoparib
14
Q

Describe TP53

A
  • TP53 = gene which makes p53 = protein
  • detects cellular stress, esp. DNA damage
  • induced G2 cell cycle arrest
  • if failure to repair damage induced apoptosis
  • TF activator
15
Q

How does p53 act in the cells

A
  • high levels of are due to inactive p53 protein
  • normal p53 regulated by negative feedback
  • high levels of p53 - accelerated ageing
  • main regulator is MDM2 - triggers degradation of p53 through ubiquitnation - occurs when p53 is not phosphorylated
  • phosphorylation disrupts p53-MDM2 complex
  • p53 becomes active and translocate to nucleus and bind to DNA - activating transcription of different genes
  • p53 self regulates own levels
16
Q

Why is p53 important?

A
  • over 50% of cancers contain mutations in the TP53 gene
  • most commonly affected TSG in cancer
  • missense mutations in hotspots
17
Q

Describe the function of the mutant p53

A
  • mutant p53 suppresses the ability of wild type p53 copy in inducing cell cycle arrest
  • mutations exert dominant activity over recessive
  • one mutation is sufficient to lose normal function
18
Q

What are current advances in treatment?

A
  • small molecules (MIRA-1, PRIMA-1) - can restore wild-type p53 functions
19
Q

Describe RB1

A
  • Gatekeeper - encodes RB protein
  • prevents cell growth by inhibiting cell cycle until cell is ready to divide
  • phosphorylation = inactivation
20
Q

What is the effect of Rb phosphorylation?

A
  • phosphorylation permits cell preparation through s phase because Rb cannot repress E2F1
  • E2F1 TF which activates genes involved in cell cycle progression
21
Q

Describe the stats of RB1

A
  • 1 in 20,000 children
  • 90% present before 5 years of age
  • treatment - surgery and radiotherapy
  • 98% cases cured
22
Q

What are the two types of retinoblastoma?

A
sporadic
- 60% of cases
- no family cases
- single tumour 
- unilateral
familial
- 30% of cases
- family history
- multiple tumours
- bilateral
23
Q

Describe second hits in retinoblastoma

A
  1. mutation or gene deletion
  2. loss of heterozygosity - by somatic recombination, gene conversion, chromosome disjunction
  3. promoter hypermethylation