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

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