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The three mechanisms for the repair of mutations?

• Direct reversal repair - reverses the damage, original genome recreated
- Mismatch repair by DNA polymerase
- Repair of UV induced pyrimidine dimers (photoreactivation)
- Repair of alkylation damage
- There are enzymes that recognise damage, and enzymes that repair.
• Excision repair - cuts out (excises) damaged region (usually along with other, non‐damaged bases), gap repaired by new synthesis of DNA
- Uses DNA polymerase and DNA ligase, i.e. the normal participants of DNA replication.
- Base Excision repair
- Nucleotide excision repair
- Methyl‐directed mismatch repair
- Translesion DNA synthesis and the SOS response
- The SOS response to excessive mutation


Direct Repair: Proofreading by DNA Polymerase

• DNA polymerase contains a ‘proof‐reader’ – a 3’‐5’ exonuclease
• Each nucleotide inserted is checked for correct base‐pairing
• Mismatched base is removed by exonuclease
• Correct base can then be inserted


Direct Repair: Photoreactivation

• In bacteria and simple eukaryotes but NOT humans
• AKA 'light repair'.
• Recall: UV light induces thymine dimers
• Photolyase binds to cross‐linked T’s, splits the cross‐link
• Reaction requires absorption of light


Direct Repair: Alkylation Damage repair

• Alkylating agents add bulky alkyl groups to bases, disrupting base‐pairing directly, eg MMS (methylmethane sulfonate, an alkylating agent).
• “Suicide” enzymes accept the alkyl group
- Ada proteins in E.coli
- Methyltransferases in humans (all types prokaryotes and eukaryotes).


DNA polymerase occasionally introduces the wrong
base when synthesizing DNA. How does DNA
polymerase correct such errors?

• DNA polymerase contains a ‘proof‐reader’ – a 3’‐5’ exonuclease.
• Each nucleotide inserted is checked for correct base‐pairing.
• Mismatched base is removed by exonuclease.
• Correct base can then be inserted.


Excision Repair: Base Excision Repair (BER)

• DNA can be chemically damaged by a variety of mechanisms
- Deamination
- Oxidation
- Alkylation
• Most common form of repair
• Damaged bases removed along with others
• Gap filled in with DNA polymerase
• Gap sealed with DNA ligase
• Does involve breakage of the phosphodiester bond.


Excision Repair: Nucleotide Excision Repair (NER)

• In most organisms
• Alternative to photoreactivation system ‐ operates in the dark (AKA dark repair)
• Removes thymine dimers and large chemical adducts
• Damage nucleotide is removed along with other adjacent nucleotides
• Mutations in NER cause the autosomal recessive Xeroderma Pigmentosum.


Excision Repair: Methyl‐directed Mismatch Repair

• Repair system that can distinguish parent strand from
daughter strand.
– Parent strand is original (non‐mutated).
– Daughter strand contains all new mutations.
• Where mismatches occur, excises region on daughter strand around the mismatch.
• In prokaryotes, DNA strands are methylated at GATC sites, shortly after replication.
• Immediately after synthesis, only the parental strand is methylated.
• During this window of time, the parent can be distinguished from the daughter.
• In E.Coli, the products of three genes, MutS, MutL and MutH, are the enzymes involved in the initial stages of mismatch repair and rely on methylation to distinguish between strands.
• Also takes place in eukaryotes but no methylation involved so still unclear how parental strand distinguished from new strand.