Chapter 9 The Mutability and Repair of DNA

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Chapter 9 The Mutability and Repair of DNA

• ??2004??????10/8/2006

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Outline
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The Mutability

• Low rates of mutation can drive evolution
• High rates of mutation can be catastrophic

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The Sources of Mutation

• DNA replication errors
• Chemical damage to the DNA
• Insertion of transposons into genes (Chapter 11)

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The Challenge for the Cell

• Scan the genome to detect errors in synthesis and
  damage to the DNA
• Mend the lesions and restore the original DNA

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The Nature of Mutations
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Some Replication Errors Escape Proofreading
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Mismatch Repair Removes Errors that Escape
Proofreading

• The mismatch repair system must rapidly find and
  repair mismatches
• It must replace the misincorporated nucleotide in
  the newly synthesized strand and not the correct
  nucleotide in the parental strand.

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Mismatch Repair Pathway for the Repair of
Replication Errors
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Dam methylation in E.coli.
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Similar Pathway in Eukaryote

• They lack MutH and E.coli.s clever trick of
  using hemimethylation to tag the parental strand.
• The Okazaki fragments play an important role.

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Hydrolysis and Deamination
That is why DNA uses T instead of U.
A and GAlso undergospontaneousdeamination
5-mC is common in vertebrate DNA, deamination
productis a natural DNA base
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Alkylation, Oxidation and Radiation
These linked bases are incapable of base-pairing
and cause stop during replication.
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Base Analogs and Intercalating Agents
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Repair of DNA Damage

• Photoreactivation
• Excision Repair System
• Recombinational Repair

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Photoreactivation
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Base Excision Repair
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DNA-glycosylase complex
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Excision Repair Pathway
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Recombination Repairs

• This is accomplished by the double-strand
  break(DSB) repair pathway.
• Although we generally consider recombination as
  an evolutionary device to explore new
  combinations of sequences, it may be that its
  original function was to repair damage in DNA.

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Translesion DNA Synthesis
How do they switch remains unknown.
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Crystal Structure of a Translesion Polymerase
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Something about Translesion Synthesis

• Because of its high error rate, translesion
  synthesis can be considered a system of last
  resort.
• The translesion polymerase are expressed as part
  of a pathway known as the SOS response.