TR

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