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10.3 DNA Damage & Cellular Repair Pathways
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9 Biochemistry: Cellular Metabolism & Bioenergetics
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10 Molecular Biology: Nucleic Acids & Genetic Technologies
10.1 Nucleic Acid Chemistry, the Double Helix & Chromatin Organisation 10.2 DNA Replication: Replisome Enzymology & Fork Dynamics 10.3 DNA Damage & Cellular Repair Pathways 10.4 The Central Dogma, Strand Nomenclature & Transcription Machinery 10.5 Post-Transcriptional Processing of Eukaryotic Pre-mRNA 10.6 Regulation of Gene Expression: Operons, Enhancers & Epigenetics 10.7 The Genetic Code, Wobble & Mutation Taxonomy 10.8 tRNA Charging & the Stages of Ribosomal Translation 10.9 Translation Inhibitors & Post-Translational Processing 10.10 Restriction Enzymes, Cloning Vectors, cDNA Libraries & PCR 10.11 Blotting, Sequencing, Microarrays & CRISPR-Cas9
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10.3 DNA Damage & Cellular Repair Pathways
Key Takeaways Explain This Topic AI
Genomic fidelity is safeguarded by five primary DNA repair pathways: DNA polymerase proofreading (3' to 5' exonuclease), Mismatch Repair (MMR, defective in Lynch syndrome), Base Excision Repair (BER, AP endonuclease), Nucleotide Excision Repair (NER, deficient in Xeroderma Pigmentosum), and double-strand break repair via Non-Homologous End Joining (NHEJ) or Homologous Recombination (HR, dependent on BRCA1/2).
Nucleotide excision repair removes bulky helix-distorting lesions, most importantly ultraviolet-induced pyrimidine dimers; loss-of-function mutations in this pathway cause xeroderma pigmentosum, in which minimal sun exposure produces severe photosensitivity and a very high skin cancer rate.
Double-strand breaks are repaired either by non-homologous end joining, which ligates the ends directly and is error-prone but available throughout the cell cycle, or by homologous recombination, which uses the sister chromatid as a template and is therefore accurate but restricted to S and G2 phases.
Last updated: September 2026
- 10.3 DNA Damage & Cellular Repair Pathways
- 4. DNA Damage and Cellular Repair Pathways
Spontaneous depurination, cytosine deamination, replication errors, reactive oxygen species (ROS), and environmental mutagens (UV light, ionizing radiation) subject every human cell to an estimated 10^4–10^5 DNA lesions per day. To prevent lethal mutagenesis, cells maintain specialized repair pathways tailored to specific biochemical lesions.
1. Polymerase Proofreading (During S Phase)
Mechanism : Replicative polymerases (Pol III in bacteria; Pol δ and ε in eukaryotes) incorporate incorrect nucleotides at a baseline frequency of roughly 10^-4 to 10^-5.
Correction : Mispaired bases fail to form correct Watson-Crick hydrogen bonds, causing the nascent 3'-terminus to fray and stall the polymerase active site. The mismatched terminus shifts into the enzyme's 3' → 5' exonuclease catalytic domain , which hydrolyzes the terminal phosphodiester bond. The strand then shifts back to the polymerase domain to resume synthesis, reducing the replication error rate to 10^-7.
2. Mismatch Repair (MMR, Post-Replication / G2 Phase)
Lesion : Corrects base-base mismatches and insertion-deletion loops that escape polymerase proofreading.
Strand Discrimination : Repair enzymes must selectively identify and excise the newly synthesized daughter strand containing the error rather than the parental template strand:
Prokaryotes : Use DNA adenine methyltransferase (Dam methylase) , which methylates the N6 position of adenines in 5'-GATC-3' palindromes. Immediately following replication, the parental strand is methylated while the nascent strand is temporarily unmethylated ( hemimethylated state ). MutS recognizes the mismatch, MutL coordinates assembly, and MutH endonuclease cleaves the unmethylated nascent strand at the hemimethylated GATC site.
Eukaryotes : Homologs MSH2/MSH6 (MutS equivalent) and MLH1/PMS2 (MutL equivalent) recognize mismatches. Strand discrimination does not rely on methylation; instead, eukaryotes utilize discontinuous nicks and free ends (such as unsealed Okazaki fragments) on the nascent lagging strand or PCNA asymmetry on the leading strand.
Clinical Pathology : Inherited germline mutations in MSH2 or MLH1 cause Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC), an autosomal dominant predisposition to early-onset colorectal, endometrial, and ovarian carcinomas characterized by genome-wide microsatellite instability (MSI) .
3. Base Excision Repair (BER, Throughout Cell Cycle)
Lesion : Non-bulky single-base chemical modifications, such as spontaneous cytosine deamination to uracil , adenine deamination to hypoxanthine, guanine oxidation to 8-oxoguanine, and base methylation.
Step-by-Step Mechanism :
DNA Glycosylase : Specific glycosylases (e.g., Uracil-DNA Glycosylase) scan DNA and cleave the β-N-glycosidic bond linking the damaged base to deoxyribose, leaving an intact sugar-phosphate backbone devoid of a base—termed an apurinic/apyrimidinic (AP) site (abasic site).
AP Endonuclease : Cleaves the phosphodiester backbone immediately 5' of the AP site.
AP Lyase / Phosphodiesterase : Cleaves the 3' side of the abasic sugar, liberating the deoxyribose-phosphate residue.
DNA Polymerase β (or Pol I) : Fills the single-nucleotide gap.
DNA Ligase : Seals the remaining phosphodiester nick.
4. Nucleotide Excision Repair (NER, G1 / Interphase)
Lesion : Corrects bulky, helix-distorting lesions that disrupt base pairing and transcription. The classic prototype is ultraviolet (UV) radiation-induced cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (covalent cross-links formed between adjacent thymine or cytosine rings on the same strand).
Mechanism :
Lesion Recognition : A multi-protein sensor complex (including XPC/XPA) detects helical distortion.
Dual Endonuclease Incision (Excinuclease) : Transcription factor IIH (TFIIH) helicase subunits (XPB and XPD) unwind the surrounding DNA. The structure-specific endonucleases (XPG at the 3' side, XPF-ERCC1 at the 5' side) make dual incisions flanking the lesion, excising an oligonucleotide of approximately 24–32 nucleotides in humans (12–13 nt in E. coli via UvrABC).
Gap Filling & Ligation : DNA Polymerase δ/ε synthesizes replacement DNA using the undamaged strand as a template, and DNA ligase seals the nick.
Clinical Pathology : Autosomal recessive mutations in any of the XP genes (XPA through XPG) cause Xeroderma Pigmentosum (XP) . Patients present with extreme photosensitivity, severe solar lentigines (freckling), corneal ulcerations, and a >1,000-fold increased risk of developing cutaneous malignancies (squamous cell carcinoma, basal cell carcinoma, and malignant melanoma) upon minimal exposure to sunlight.
5. Double-Strand Break (DSB) Repair: NHEJ vs. Homologous Recombination
Double-strand breaks represent the most hazardous genotoxic lesion: failure to repair them causes chromosome fragmentation, translocations, and cell death. Cells employ two distinct repair strategies:
Non-Homologous End-Joining (NHEJ) :
Cell Cycle Phase : Active predominantly during G1 phase when sister chromatids are absent.
Mechanism : The Ku70/Ku80 heterodimer binds exposed DNA double-strand ends, recruits DNA-PKcs (DNA-dependent protein kinase), and aligns broken ends. Nucleases (Artemis) process and resect damaged microhomology termini, and specialized DNA Ligase IV seals the break.
Fidelity : Inherently error-prone (mutagenic) . NHEJ introduces small insertions or deletions (indels) at the repair junction and can join unrelated chromosomal fragments, generating translocations. NHEJ also functions physiologically during V(D)J recombination in lymphocyte antigen receptor maturation.
Homologous Recombination (HR) :
Cell Cycle Phase : Active strictly during late S and G2 phases , when an identical sister chromatid is available as a repair template.
Mechanism : The MRN complex and CtIP resect the 5' ends of the break, creating 3' single-stranded DNA overhangs. BRCA1 , BRCA2 , and RAD51 recombinase coat the ssDNA, promoting strand invasion (D-loop formation) into the homologous sister chromatid duplex. DNA polymerase copies information from the undamaged sister chromatid across the break, and resolving enzymes separate the resulting Holliday junctions.
Fidelity : Error-free repair . Germline loss-of-function mutations in BRCA1 or BRCA2 disable homologous recombination, forcing cells to rely on error-prone NHEJ and alternative pathways. This drives genomic instability, sharply elevating the lifetime incidence of hereditary breast, ovarian, prostate, and pancreatic carcinomas.
Summary of Major DNA Repair Pathways
Repair Pathway Cell Cycle Phase Primary Lesions Repaired Key Enzymes & Proteins Clinical Disease / Pathology
Polymerase Proofreading S phase Base misincorporations 3' → 5' Exonuclease of Pol III / Pol δ/ε Elevated spontaneous mutation rate
Mismatch Repair (MMR) G2 / Post-replication Replication slippage, uncorrected mismatches MSH2, MLH1, PMS2, MSH6 (Prokaryotes: MutS, MutL, MutH) Lynch Syndrome (HNPCC) , Microsatellite Instability (MSI)
Base Excision Repair (BER) Throughout cell cycle (G1, G2) Deaminated bases (U in DNA), oxidized bases (8-oxoG), alkylated bases DNA Glycosylase, AP Endonuclease, AP Lyase, Pol β, Ligase Increased somatic mutations; neurodegenerative disorders
Nucleotide Excision Repair (NER) G1 / Interphase Bulky adducts, UV-induced thymine-thymine cyclobutane dimers XPA–XPG proteins, TFIIH helicase, Excinuclease, Pol δ/ε, Ligase Xeroderma Pigmentosum (XP) ; extreme UV photosensitivity & skin cancer
Non-Homologous End Joining (NHEJ) G1 phase Double-strand breaks (DSBs) Ku70/80, DNA-PKcs, Artemis, DNA Ligase IV Immunodeficiency (SCID due to defective V(D)J recombination)
Homologous Recombination (HR) Late S / G2 phase Double-strand breaks, inter-strand crosslinks MRN complex, BRCA1, BRCA2, RAD51, DNA Pol δ/ε Familial Breast & Ovarian Cancer (BRCA1/2 mutations)