Summary of DNA Repair and Genetic Recombination
DNA Repair and Genetic Recombination: A Student's Guide
Introduction
DNA repair encompasses multiple cellular systems that detect and correct damage to DNA, preserving genome integrity and preventing mutations that can lead to disease. This material summarizes the major DNA-repair pathways in prokaryotes and eukaryotes (excluding detailed coverage of DNA recombination), explains mechanisms, and gives practical examples and clinical relevance.
Definition: DNA lesion — an unrepaired physical or chemical change in DNA that can become a permanent mutation if not corrected.
1. Why DNA repair matters
- Cells experience thousands of DNA lesions daily from replication errors, spontaneous chemical reactions, UV light, ionizing radiation, and environmental mutagens.
- Most lesions affect only one strand and can be fixed using the opposite strand as a template.
- Failure to repair leads to permanent mutations, which can drive cancer and inherited disease.
💡 Věděli jste?Did you know that of the many thousands of DNA lesions per cell per day, thanks to repair systems fewer than 1 in 1000 become permanent mutations?
2. Overview of major repair pathways
Use this table to compare core pathways.
| Pathway | Main target | Key initiating proteins (bacteria/eukaryotes) | End result |
|---|---|---|---|
| Mismatch repair (MMR) | Replication mismatches, small insertion/deletion loops | MutS/MutL/MutH (bacteria); MSH2/MSH6, MSH2/MSH3, MLH1/PMS1 (eukaryotes) | Removal of error-containing strand segment and resynthesis |
| Base excision repair (BER) | Single damaged bases (deamination, oxidation, alkylation) | Specific DNA glycosylases, AP endonuclease, DNA Pol I (bacteria) | AP site creation, excision, fill-in, ligation |
| Nucleotide excision repair (NER) | Bulky helix-distorting lesions (pyrimidine dimers, bulky adducts) | UvrA/B/C/D (bacteria); multiple factors in eukaryotes | Dual incision around lesion, removal, resynthesis |
| Direct repair | Certain specific lesions (photodimers, O6-methylguanine) | Photolyase (in many organisms), O6-methylguanine methyltransferase | Direct chemical reversal of lesion |
| Translesion synthesis (TLS) | Replication-blocking lesions when repair incomplete | Error-prone polymerases (Pol V, Pol IV in bacteria; specialized TLS polymerases in eukaryotes) | Synthesis across lesion with increased mutation rate |
| Nonhomologous end joining (NHEJ) | Double-strand breaks when no template available | Ku70/80, DNA-PKcs, Artemis, Ligase IV (eukaryotes) | End-joining that may alter sequence |
3. Mismatch Repair (MMR)
Bacterial MMR (E. coli)
- Detection: MutS scans double-stranded DNA and binds mismatches (except C•C). MutL then joins and recruits MutH.
- Strand discrimination: E. coli uses adenine methylation of GATC motifs by Dam methylase. After replication, hemimethylated GATC identifies the newly synthesized (unmethylated) strand as the one to correct.
- Excision: Activated MutH is an endonuclease that nicks the unmethylated daughter strand near a GATC. Helicase II (UvrD) and exonucleases degrade from the nick toward the mismatch. Which exonuclease acts depends on orientation:
- If mismatch is 3' to the nick, RecJ (5'→3' exonuclease) removes bases.
- If mismatch is 5' to the nick, Exonuclease I or X (3'→5') removes bases.
- Exonuclease VII can act bidirectionally.
- Resynthesis and ligation: DNA Pol III fills the gap; DNA ligase seals the nick.
- Note: MMR can remove long tracts (hundreds to thousands of nucleotides), consuming energy.
Eukaryotic MMR
- Homologs: MSH2, MSH3, MSH6 (MutS-like) and MLH1/PMS1 (MutL-like). No MutH homolog and no hemimethylated GATC signaling.
- Specificity:
- MSH2/MSH6 recognizes base–base mismatches and small insertion/deletion loops.
- MSH2/MSH3 handles larger loops.
- Clinical relevance: Germline mutations in MMR genes (e.g., MLH1, MSH2) cause hereditary nonpolyposis colorectal cancer (HNPCC / Lynch syndrome).
💡 Věděli jste?Fun fact: Defects in mismatch repair raise mutation rates and are a major cause of early-
Zaregistruj se pro celé shrnutíFlashcardsKnowledge testSummaryPodcastMindmap
Start for free Already have an account? Sign in
DNA Repair Overview
Klíčové pojmy: DNA lesions are repaired by distinct pathways matched to lesion type, Mismatch repair uses strand-discrimination; bacteria use hemimethylated GATC, Base excision repair removes single damaged bases via glycosylases and AP endonucleases, Nucleotide excision repair removes bulky, helix-distorting lesions via dual incisions, Direct repair chemically reverses some lesions (photolyase, MGMT, AlkB), Translesion synthesis allows replication across lesions but is error-prone, NHEJ repairs double-strand breaks without a template and can alter sequence, Defects in repair pathways cause human diseases: XP (NER), HNPCC (MMR), Ames test detects mutagenicity using reversion in Salmonella, Eukaryotes lack MutH and use MSH/MLH homologs for mismatch recognition, BER resynthesis uses DNA polymerase activity plus ligase to seal nicks, TLS polymerases in eukaryotes (e.g., Pol η) can be lesion-specific and reduce mutation rate
## Introduction
DNA repair encompasses multiple cellular systems that detect and correct damage to DNA, preserving genome integrity and preventing mutations that can lead to disease. This material summarizes the major DNA-repair pathways in prokaryotes and eukaryotes (excluding detailed coverage of DNA recombination), explains mechanisms, and gives practical examples and clinical relevance.
> Definition: DNA lesion — an unrepaired physical or chemical change in DNA that can become a permanent mutation if not corrected.
## 1. Why DNA repair matters
- Cells experience thousands of DNA lesions daily from replication errors, spontaneous chemical reactions, UV light, ionizing radiation, and environmental mutagens.
- Most lesions affect only one strand and can be fixed using the opposite strand as a template.
- Failure to repair leads to permanent mutations, which can drive cancer and inherited disease.
Did you know that of the many thousands of DNA lesions per cell per day, thanks to repair systems fewer than 1 in 1000 become permanent mutations?
## 2. Overview of major repair pathways
Use this table to compare core pathways.
| Pathway | Main target | Key initiating proteins (bacteria/eukaryotes) | End result |
|---|---:|---|---|
| Mismatch repair (MMR) | Replication mismatches, small insertion/deletion loops | MutS/MutL/MutH (bacteria); MSH2/MSH6, MSH2/MSH3, MLH1/PMS1 (eukaryotes) | Removal of error-containing strand segment and resynthesis |
| Base excision repair (BER) | Single damaged bases (deamination, oxidation, alkylation) | Specific DNA glycosylases, AP endonuclease, DNA Pol I (bacteria) | AP site creation, excision, fill-in, ligation |
| Nucleotide excision repair (NER) | Bulky helix-distorting lesions (pyrimidine dimers, bulky adducts) | UvrA/B/C/D (bacteria); multiple factors in eukaryotes | Dual incision around lesion, removal, resynthesis |
| Direct repair | Certain specific lesions (photodimers, O6-methylguanine) | Photolyase (in many organisms), O6-methylguanine methyltransferase | Direct chemical reversal of lesion |
| Translesion synthesis (TLS) | Replication-blocking lesions when repair incomplete | Error-prone polymerases (Pol V, Pol IV in bacteria; specialized TLS polymerases in eukaryotes) | Synthesis across lesion with increased mutation rate |
| Nonhomologous end joining (NHEJ) | Double-strand breaks when no template available | Ku70/80, DNA-PKcs, Artemis, Ligase IV (eukaryotes) | End-joining that may alter sequence |
## 3. Mismatch Repair (MMR)
### Bacterial MMR (E. coli)
- **Detection:** MutS scans double-stranded DNA and binds mismatches (except C•C). MutL then joins and recruits MutH.
- **Strand discrimination:** E. coli uses adenine methylation of GATC motifs by Dam methylase. After replication, hemimethylated GATC identifies the newly synthesized (unmethylated) strand as the one to correct.
- **Excision:** Activated MutH is an endonuclease that nicks the unmethylated daughter strand near a GATC. Helicase II (UvrD) and exonucleases degrade from the nick toward the mismatch. Which exonuclease acts depends on orientation:
- If mismatch is 3' to the nick, RecJ (5'→3' exonuclease) removes bases.
- If mismatch is 5' to the nick, Exonuclease I or X (3'→5') removes bases.
- Exonuclease VII can act bidirectionally.
- **Resynthesis and ligation:** DNA Pol III fills the gap; DNA ligase seals the nick.
- **Note:** MMR can remove long tracts (hundreds to thousands of nucleotides), consuming energy.
### Eukaryotic MMR
- Homologs: MSH2, MSH3, MSH6 (MutS-like) and MLH1/PMS1 (MutL-like). No MutH homolog and no hemimethylated GATC signaling.
- Specificity:
- MSH2/MSH6 recognizes base–base mismatches and small insertion/deletion loops.
- MSH2/MSH3 handles larger loops.
- Clinical relevance: Germline mutations in MMR genes (e.g., MLH1, MSH2) cause hereditary nonpolyposis colorectal cancer (HNPCC / Lynch syndrome).
Fun fact: Defects in mismatch repair raise mutation rates and are a major cause of early-