Loss of function mutations (tumour-suppressor genes)

• Loss-of-function mutations leads to:

  • reduced amount of proteins due to decreased transcription -> leads to decrease in translation (protein synthesis)
  • proteins with reduced activity or non-functional due to changes to the 3D conformation of the protein that abolish function
• Tumour suppressor genes function to inhibit uncontrolled cell division -> LOF mutation of a tumour suppressor gene = loss in ability to inhibit uncontrolled cell division -> uncontrolled cell division
• Tumour suppressor proteins include those that:

  1. detect DNA damage at the checkpoints and halt the cell cycle -> allow time for DNA repair
  2. repair damaged DNA and prevent cell from accumulating cancer-causing mutations
  3. control adhesion of cells to each other or the extracellular matrix
  4. receptors for hormones that function to inhibit cell proliferation
  5. activate apoptosis -> prevent cells with DNA damage to continue to divide and pass on the defects to daughter cells -> prevent accumulation of additional mutations that will lead to the formation of a tumour
• • NORMAL tumour suppressor genes are dominant alleles
  • MUTATED tumour suppressor genes are recessive alleles
• In heterozygote:

  • the single normal copy of the tumour suppressor gene is sufficient to synthesise enough proteins to inhibit cell proliferation
  • dominant normal tumour suppressor allele masks the effect of the recessive mutated tumour suppressor allele
• For cancerous cell to develop -> both alleles of a tumour suppressor gene must be mutated + unable to produce protein required to inhibit cell division
• LOF mutation can occur in various ways:

  1. Mutations in promoters or control elements
  2. Mutations within tumour suppressor gene
  3. chromatin modifications
• (1) Mutations in promoters or control elements -> lead to down-regulation (decreased expression) of tumour suppressor gene expression
• (2) Consequences of Mutations within tumour:

  • no protein produced
  • production of protein that binds to its substrate with decreased affinity
  • production of a non-functional protein due to loss of protein structure
• (3) Chromatin modifications

  • high level of histone deacetylase expressed by tumour cells -> deacetylates histones, increase positive charge on histone protein -> DNA coiling tightly around histones -> TS genes are silenced
  • excessive histone methylation/packaging of genes as heterochromatin -> effectively shut down gene expression of TS genes