Mismatch Repair
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DNA REPLICATION: FACTORS THAT INCREASE FIDELITY
• Increase fidelity to 1 mistake per 10^9 bases added
1. DNA Pol. proofreading capacity
• DNA Pol. 3' to 5' exonuclease activity: can excise/replace incorrect nucleotides
• Prokaryotes: DNA Pol. I (replaces RNA primers) & III (daughter strands) are exonucleases
• Eukaryotes: DNA Pol. delta (lagging strand) & epsilon (leading strand) are exonucleases
2. Repair mechanisms
Mismatch repair: identifies/fixes replication errors that escape DNA Pol.
• Addresses single-strand breaks in newly replicated DNA
• Cannot repair DNA Damage
MISMATCH REPAIR: E. COLI
• Mismatched nucleotides cannot H-bond --> distorts DNA
• GATC sequence occurs about every thousand nucleotides
• A in GATC is methylated: distinguishes parent strand from daughter strand
• Mut proteins (mismatch repair enzymes in E. Coli)
1. MutS recognizes mismatched base and initiates repair by binding
2. MutS forms complex with MutL
3. MutL binding activates endonuclease MutH
4. MutH cleaves daughter strand opposite to adenine-methylation (GATC)
5. Exonuclease and helicase excise portion of daughter strand
Intertextual variation exits regarding above step.
6. DNA Pol. (III or I) fills gap and ligase seals ends w/ phosphodiester bonds
• DNA Pol synthesizes gap in 5' to 3' direction
MISMATCH REPAIR: HUMANS
• MSH proteins: human homologs for Mut proteins (no MutH homolog)
• Daughter strand specificity poorly understood: not adenine-methylation
Theoretical recognition sites: breaks in lagging strand & lengthening 3' end of lagging strand.
• DNA Pol. (delta and epsilon) fill excised gap
CLINICAL CORRELATION
Lynch Syndrome
• Formerly known as hereditary nonpolyposis colorectal cancer (HNPCC)
• Mutation in human Mut homologs: defective mismatch repair pathway
• Increased risk for colorectal and other cancers
• ~ 3 in every 100 cases of colon cancer caused by Lynch syndrome