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Mutations, Mutagenesis, and Repair

Mutations, Mutagenesis, and Repair. Chapter 10. The Problem. DNA extremely long, fragile Subject to both physical and chemical damage Consequences could be lethal for organism or offspring. }. Frameshift mutations. Mutation. A heritable change in the base sequence of DNA

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Mutations, Mutagenesis, and Repair

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  1. Mutations, Mutagenesis, and Repair Chapter 10

  2. The Problem • DNA extremely long, fragile • Subject to both physical and chemical damage • Consequences could be lethal for organism or offspring

  3. } Frameshift mutations Mutation • A heritable change in the base sequence of DNA • Point mutation- change in a single base position • Additions • Deletions • Substitutions • Transitions • Transversions • Multiple mutations

  4. Consequences of Mutation • Silent Mutation---base change, no amino acid change • Neutral Mutation--- Base change resulting in aa change that does not affect protein function • EX. Apartic acid (D) Glutamic acid (E) • Missense mutation---altered codon, new aa with different chemical properties. Function affected. • Nonsense mutation---base pair substitution results in a stop codon (and shorter polypeptide) • Frameshift mutations—additions or deletions. Peptide may be longer or shorter. • Sense mutation?

  5. Other Terms • Conditional Mutation—wild type function except under certain (permissive) conditions • Ex. Temperature sensitive mutants show mutant phenotype only at certain temperatures • Leaky mutations— a missense amino acid change that reduces but doesn’t eliminate protein function

  6. Mutagenesis • The process of mutation • Mutagen—anything that promotes ort causes mutations • Chemical • Physical

  7. Mutation-Causes • Incorrect base pairing due to tautomeric shifts • Removal of nitrogenous bases • Alteration of nitrogenous bases • Addition or deletion of nucleotides • Single strand breaks • Double strand breaks • Crosslinking—covalent linkage between bases

  8. Spontaneous Mutations • Arise without mutagenic agents. DNA pol has proofreading function, can remove mismatched base • Even if DNA pol misses a mismatch other systems can recognize and repair it. • Recognition? • Hemimethylation-allows enzymes to distinguish between parent and daughter strands.

  9. } Altered H-bonding Spontaneous Mutations • Tautomeric shifts during replication. • Depurination—if a purine base is lost from C-1 of deoxyribose, will get apurinic site. • Odds of misincorporation on the daughter strand=75% • Enzymes specific for this type of mutation have evolved • Deamination. • CU • AHypoxanthine

  10. Tautomers and Mutation Normal base pairing Rare imino forms of adenine and cytosine Rare enol forms of thymine and guanine Back

  11. Deamination of C and A • CU • 3 H-bonds w/G2 H-bonds w/A • AHypo-xanthine • 2 H-bonds w/G3 H-bonds w/C

  12. Removing and Replacing Uracil • Uracil automatically removed from DNA by uracil N-glycosylase • AP Endonuclease cuts 5’ to apurinic site • Sugar phosphate removed by phosphodiesterase • DNA pol I adds correct base • Ligase seals • Base Excision Repair (BER)

  13. G G P P P P P P P P P P P P P P P P T C G T U C G A G C A G G C A G C A C P P P P P P P P P P P P P P Base Excision Repair (BER) Uracil DNA glycosylase AP endonuclease G DNA polymerase I G T C C G DNA ligase T G

  14. 5 Methyl Cytosine Deamination • Easily recognized and corrected • What about 5-methyl cytosine? • Is there a problem? • Always remove T from a GT pair ?

  15. Deamination of Cytosine and 5-methylcytosine -------------------------------------------------------------------------------

  16. Induced Mutations • Caused by exposure to a mutagen • Causes • Exposure to base analogs • Chemical mutagens • Intercalating agents • Uv- radiation • Transposable elements • Mutator genes

  17. Exposure to Bases Analogs • Base analogs—substances that are similar to and can substitute for standard bases • Examples—AZT, 5-bromouracil (5-BU) and 2-aminopurine (2-AP)

  18. 5 Bromouracil THE PROCESS A·T • The Problem: 5 bromouracil assumes the enol form at a much higher frequency than T • if it replaces T, will probably get a mutation due to tautomerization during replication • Result: A·T G·C Replication in presence of BrU A·BrU Tautomeric shift A·BrU* Replication A·T + G·BrU* Replication A·T + A·T + G·BrU* + GC

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