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
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