DNA Damage

Mutation

• Mutation: a heritable change in the genetic material
• Essential to the continuity of life
• Source of variation for natural selection
• New mutations are more likely to be harmful (or have zero effect) than beneficial
• DNA repair systems reverse DNA damage
• Cancer is a disease caused by gene mutations

Causes of DNA Damage

• Copying Error from DNA Polymerase
  • DNA Pol a and e have 3’-5’ exonuclease activity
• Chemical Damage
  • Endogenous (radicals formed as a result of metabolism)
  • Exogenous (environmental)
  • Ames Test
• Radiation Damage
  • Ionizing radiation causes DNA breaks
  • U.V. radiation causes DNA distortions (T-C, C-C, T-T dimers)

Types of DNA Damage

• Point mutations
  • Deamination
  • Depurination
  • Depyrimination
• DNA distortions (T-C, T-T dimers)
• Interstrand Crosslinks
• DNA-protein crosslinks
• Strand breaks (single strand breaks aren’t a problem but double strand breaks are)

Gene Mutations May Affect Amino Acid Sequences

• Silent Mutation: does not alter the amino acid sequence
  • Due to degeneracy of genetic code
• Missense Mutation: changes a single amino acid in a polypeptide
  • May not alter function if substituted amino acid is similar in chemistry to original
  • ex: Sickle-cell disease
• Nonsense Mutation: change from a normal codon to a stop codon
  • Produces a truncated polypeptide
• Frameshift Mutation: addition or deletion of nucleotides (excluding multiples of 3)
  • Completely different amino acid sequence downstream from mutation

Gene Mutations Outside of Coding Sequences

• A mutation may alter the sequence within a promoter and affect the rate of transcription
  • May enhance or inhibit transcription
• Mutations may occur in other regulatory elements or operator sites
  • Mutation may alter DNA sequence of operator so that repressor protein does not bind

Germ-line or Somatic Cell Mutations

• The time and location of a mutation determines its severity and the heritability

• Germ-line cells give rise to gametes

  • Mutation can occur in sperm or egg cell, or in gamete progenitor cells

• Somatic cells are all other body cells

  • Can occur early or late in development
  • Gives a genetic mosaic with patches of mutant tissue

Mutagens Alter DNA

• Disruption of base pairing

  • Some modify nucleotide structure
  • Nitrous acid deaminates bases, changing C to U, so that it pairs with the wrong nucleotide
  • Mustard gas or EMS alkylate bases, adding methyl or ethyl groups
  • Base analogues substitute into DNA

• Disruption of replication

  • Some insert between the bases and distort the helix
  • Benzopyrene, found in cigarettes and charbroiled food

Physical Mutagens

• Radiation Damage
  • Ionizing radiation has high energy and penetrates deeply to create free radicals
  • X rays and gamma rays
  • Cause deletions or breaks in one or both DNA strands
  • Nonionizing radiation has less energy and can only penetrate the surface
  • UV rays can cause formation of thymine dimers, causing gaps or incorporation of incorrect bases