DNA Repair Pathways & Clinical Pathologies
| Repair Pathway | Specific Lesion Targeted | Key Enzymes & Mechanism | Associated Clinical Disease |
|---|---|---|---|
| Nucleotide Excision Repair (NER) | Bulky, helix-distorting lesions. Primarily, pyrimidine (UV thymine) dimers are caused by ultraviolet radiation. | Specific Endonucleases cleave the damaged strand on both sides of the lesion; an oligonucleotide fragment is excised. DNA Polymerase and Ligase fill and seal the gap. Occurs in the G1 phase of the cell cycle. | Xeroderma Pigmentosum (Severe sun sensitivity, early skin malignancies, dry skin). |
| Base Excision Repair (BER) | Non-bulky base damage. **Spontaneous deamination** (e.g., cytosine converting to uracil), oxidation, alkylation, or nitric oxide damage. | 1. Base-specific Glycolylase removes an altered base, creating an AP site. 2. AP-Endonuclease cleaves the 5′ end. 3. Lyase cleaves the 3′ end. 4. DNA Polymerase-β fills the gap. 5. Ligase seals. Occurs **throughout the cell cycle**. |
Essential to combat daily oxidative damage and prevent spontaneous mutagenesis. |
| Mismatch Repair (MMR) | Unmethylated, mispaired bases and small insertions/deletions that escape DNA polymerase proofreading during replication. | Mismatch recognized by specialized proteins (MSH2, MLH1). The unmethylated newly synthesized strand is identified, cleaved, and degraded. Filled by DNA Polymerase and sealed by Ligase. Occurs in S phase. | Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer [HNPCC]; characterized by microsatellite instability). |
| Non-Homologous End Joining (NHEJ) | Double-strand DNA breaks (DSBs) are caused by ionizing radiation, free radicals, or chemotherapeutic drugs. | Re-ligates two broken DNA ends directly without a homologous template. **Error-prone**; frequently results in the loss or insertion of a few nucleotides. Utilizes **Ku70/Ku80** heterodimer and DNA-PKcs. | Ataxia-Telangiectasia (ATM gene mutation; ataxia, telangiectasia, immunodeficiency) Severe Combined Immunodeficiency (SCID) |
| Homologous Recombination (HR) | Double-strand DNA breaks (DSBs). | Uses the sister chromatid or homologous chromosome as a template to guide perfectly accurate repair. **Error-free** mechanism. Requires **BRCA1, BRCA2**, and Rad51 proteins. Occurs strictly in **S and G2 phases**. | Hereditary Breast & Ovarian Cancer (BRCA1/BRCA2 mutations) Fanconi Anemia |
High-Yield Core Realities:
- G1 vs. S vs. G2 Phase Segregation: Nucleotide Excision Repair repairs UV damage in G1 before replication begins. Mismatch Repair checks the freshly replicated DNA during S phase. Homologous Recombination requires an intact duplicate sister chromatid template, restricting its functionality to late S and G2 phases. Base Excision Repair operates continuously throughout all phases to handle metabolic oxidative damage.
- The Base Excision Repair Order of Operations: Memorizing the acronym **GEL PLease** or tracking the sequential enzymatic logic is vital for boards: **G**lycolylase (removes base) → **E**ndonuclease (cuts 5′ side) → **L**yase (cuts 3′ side) → **P**olymerase (fills) → **L**igase (seals).
- Microsatellite Instability (MSI) Tracking: Microsatellites are short, repetitive, non-coding DNA sequences scattered across the genome. When Mismatch Repair is defective (as in Lynch syndrome), DNA polymerase routinely slips during replication of these repeats, leading to dynamic variations in their lengths across cell generations. MSI serves as the classic molecular signature for MMR pathobiology.
- Double-Strand Break Deficit Distinctions: Both NHEJ and HR resolve catastrophic double-strand breaks. NHEJ does not require a template and operates during G1, making it fast but mutagenic. HR achieves flawless fidelity by using a sister chromatid template, meaning it is unavailable during G1. Defective NHEJ directly impairs **V(D)J recombination** and class-switch recombination in developing B and T cells, underlying severe primary immunodeficiencies.