eBook Chapter 6 - Tumour Suppressor Genes

Question 1

Describe briefly the characteristics of tumour suppressor genes

Answer 1

• protein products of TSGs negatively regulate the cell cycle, are components of cell cycle checkpoints that ensure genomic integrity in response to genotoxic stress
• loss of TSG functions may occur either through genetic mutation or the epigenetic silencing of genes via promotor methylation
• recessive - both alleys of TSG must be eliminated or inactivated
• two hit hypothesis

Question 2

What is the function of pRB in normal cells

Answer 2

• involved in control of the cell cycle
• restriction point that controls progression from G1 –> S
• pRB functions as a transcriptional repressor during cell cycle
• acts by binding or releasing E2F transcription factors associated with promoters of genes triggering transition of the cell from G1 to S
• hypophosphorylated pRB bunds E2Fs and hyperphosphorylated pRB releases them

Question 3

How is pRB regulated?

Answer 3

• regulated through phosphorylation,

Question 4

What is the function of p53?

Answer 4

• sequence-specific transcription factor, possess pro-apoptotic and growth arresting activities; it induces cellular sentence and inhibits angiogenesis
• p53 can impose cell cycle arrest through p21
• when cellular stress occurs, p52 causes cell to enter quienscnece or even apoptosis
• apoptosis is characterised by activation of a cascade of camasses resulting in cell destruction

Question 5

How is p53 controlled?

Answer 5

• two critical upstream regulators
• MDM2: binds to p53, blocking p53 driven transcription, directs ubiquitylation of p53 and its export to cytoplasm and degradation in the proteasome
• p19ARF: inhibits MDM2 thus allowing rapid increase in p53 levels

Question 6

What are the overall functions of BRCA1 and BRCA2?

Answer 6

• both involved in DNA damage response
• act partially as scaffold to assemble large DNA repair complexes
• loss of one of both realists in increased sensitivity of cell to ionising radiation

Question 7

What are the specific functions of BRCA1?

Answer 7

• cell cycle checkpoint protein
• S- phase checkpoints via BACH1, TopBP1
• G2/M checkpoints via CtlP, MRN
• homologous recombination via BRCA2, Rad51

Question 8

What are the specific functions of BRCA2?

Answer 8

• modulate DNA double strand break repair through its interaction with Rad51 in recombination repair

Question 9

What are the different histological characteristics of BRCA1 and BRCA2 tumours?

Answer 9

BRCA1 = higher mitotic rate and more lymphocyte infiltration  
BRCA2 = higher tubule formation