chapter 14 molecular mechanisms of mutation and dna repair jones and bartlett publishers © 2005
TRANSCRIPT
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Chapter 14
Molecular Mechanisms of Mutation and DNA Repair
Jones and Bartlett Publishers © 2005
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Definitions
• Mutation = an inherited change in the genetic material of an organism.
• Mutagens vs. teratogens
• Germline vs. somatic mutation
• Spontaneous vs. induced mutations
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Types of Mutations
• Most common – base-pair substitutions
– Transition mutations – Pu to Pu, Py to Py.• GA & A G
• T C & C T
– Transversion mutations – Pu to Py or Py to Pu.• A T, A C, G T, or G C.
• T A, T G, C A, or C G.
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Types of Mutations
• Neutral mutations result when amino acid substitutions do not change protein function.
• Similar amino acids can be substituted for each other – isoleucine for leucine.
• Missense mutations result when the amino acid substitution changes protein function.– Temperature sensitivity often is a missense
mutation.
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Types of Mutations
• Nonsense mutations – change in codon to UGA, UAA, or UAG.
• This results in premature stopping of protein synthesis.
• They can be lethal or severe in phenotype.
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Types of Mutations
• The 2nd most common type of mutations are insertion/deletions of base pairs.
• This can cause frameshifts.
• Deletions or insertions of one or two bases usually results in dramatic differences in protein production.
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Types of Mutations
• Why are these mutations important? – They can affect mRNA and protein production,
eventually determining the phenotype.
• Silent mutations – produce no change in amino acid sequence (due to degeneracy of the genetic code.) (aka synonymous mutations).– CUU codes for leucine, but so does CUC, CUA,
CUG, UUA, and UUG.
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A single base pair mutation in the -globin gene changes one amino acid in the coded protein
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A base pair addition/deletion (frameshift) mutation results in multiple amino acid changes downstream from the point of mutation
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Types of DNA Replication Errors
• Tautomeric shifts lead to mismatched bases.
• DNA slippage – runs of the same base, or repeated sequences.
• Depurination and deamination
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The inheritance of the fragile-X syndrome (caused by expansion of triplet repeats CGG)
With each passing generation, the number of triplets increases. Once a threshold number of repeats is reached, the disease phenotype becomes visible. In this pedigree, such a value is reached in generation 3.
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Triplet repeat mutations are created by template slippage during DNA replication
followed by mismatch repair
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Part of a messenger DNA containing a G quartet
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Insertion of a transposon creates short direct repeats in the target DNA flanking the inserted transposon
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Definition of direct and inverted repeat DNA sequences
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Structure of a retrotransposon (retrovirus genomes also have direct repeats at the ends)
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Recombination between 2 transposons in the same DNA molecule has different consequence
depending upon their relative orientation
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Recombination between transposons in 2 different DNA molecules can lead to duplication or deletion mutations
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The technique of replica plating proves that mutations arise spontaneously rather
than being induced by a selective agent
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A method for detecting recessive lethals on the X-chromosome in Drosophila
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5-methylcytosines are hot spots of mutation-1
The mechanism of methylation of cytosine
in the 5-position
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5-methylcytosines are hot spots of mutation-2
Deamination of cytosine leads to
uracil while deamination
of 5-methyl-cytosine leads to
thymine
Uracil is not a normal
component of DNA and can be recognized and
removed. Thymine is a
normal component of
DNA and is not recognized as a
source of potential mutation.
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Excision repair of uracil in DNA
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Mechanism of mutagenesis by the tautomerization of the thymine analog 5-Bromouracil
The keto and enol forms of DNA
bases are called
tautomers. Both thymine and
5-bromouracil can assume these 2
alternative states.
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Base analogs like 5-bromouracil can induce mutations
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Structure of 2 alkylating mutagens
It resembles a base pair
Structure of a frameshift mutagen
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Ultraviolet light causes joining (crosslinking) of adjacent pyrimidine bases
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Induction of mutations by radiation is linearly related to exposure dose
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Annual exposure of human beings in the United States to various forms of ionizing radiation
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People exposed to increased radiation from the Chernobyl accident have a doubling of mutation rate
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A low spontaneous mutation rate is achieved by 3 successive accuracy-enhancing steps
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Mechanism of post-replication mismatch correction based on the methylation of the parental DNA strand
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Steps in the excision repair of an apurinic or apyrimidinic (AP) site
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Repair of a bubble created in DNA by the addition of a bulky agent
There is a mistake in this diagram. The damaged
segment is displaced by a DNA helicase (not a DNA polymerase). During the
displacement of a strand by a DNA polymerase, DNA
synthesis is concerted with strand displacement and no
gap is formed.
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Repair of a damage site by recombinational repair
Recombinational repair is used when excision
repair fails
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Restoration of the wild type phenotype by a second mutation compensating for the first mutation
A mutation that rescues another
mutation is called a suppressor
mutation
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The Ames test for the detection of a chemical mutagen
Most chemicals that act as mutagens in
bacteria cause cancer in animals
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Chapter 15
• Cell cycle regulation via checkpoints
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• Transcriptional activation via p53 protein.
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• Sporadic (99%) vs. familial (1%) cancers
– Contact inhibition
– Cell senescence (associated with telomerase activity; higher in cancer cells)
– Cancers are clonal.
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Oncogene- assoc. with tumor progression