Nucleotide Excision Repair (NER) DNA repair mechanism that detects and removes bulky, helix-distorting lesions from DNA, such as those caused by UV radiation , chemical adducts , and environmental mutagens . It works by excising a short single-stranded DNA segment containing the damage and replacing it using the undamaged strand as a template .
Key Functions: Repairs thymine dimers and 6-4 photoproducts caused by UV light . Fixes chemical adducts (e.g., those caused by carcinogens like benzopyrene). Essential for genomic stability , cancer preventioncell survival Steps in NER (Generalized): Damage Recognition :Specialized proteins scan the DNA for distortions in the helix , not the specific base changes. Two pathways detect damage:Global Genome NER (GG-NER) : Scans the entire genome.Transcription-Coupled NER (TC-NER) : Targets DNA damage that blocks transcription. DNA Unwinding :TFIIH complex (includes XPB and XPD helicases) unwinds the DNA around the lesion to form a bubble .Excision of Damaged Strand :Endonucleases (e.g., XPF-ERCC1 and XPG ) cut the damaged strand on both sides of the lesion (~24–32 nucleotides). DNA Synthesis :DNA polymerase fills in the gap using the complementary strand as a template . Ligation :DNA ligase seals the final phosphodiester bond , restoring the DNA backbone. Key Proteins in NER (Human): Protein /ComplexRole XPC Damage recognition (GG-NER) CSA/CSB Damage recognition (TC-NER) TFIIH DNA unwinding via XPB and XPD XPA Damage verification RPA Stabilizes single-stranded DNA XPF-ERCC1 / XPG 5′ and 3′ endonucleases DNA polymerase δ/ε Gap filling DNA ligase I or III Strand sealing
Types of NER Pathways: Type Focus Trigger Global Genome NER (GG-NER) Scans the entire genome General DNA damage Transcription-Coupled NER (TC-NER) Prioritizes active genes Stalled RNA polymerase at lesions
Clinical Relevance: Condition Cause Description Xeroderma Pigmentosum (XP) Mutations in NER genes (e.g., XPA, XPC, XPD) Extreme sensitivity to UV, high cancer risk Cockayne Syndrome (CS) Defects in TC-NER (CSA, CSB) Growth failure, neurodegeneration, premature aging Trichothiodystrophy (TTD) Mutations in TFIIH components Brittle hair, intellectual disability, photosensitivity
Summary Table: Feature Description Purpose Remove bulky DNA lesions Damage Type Repaired UV-induced lesions, chemical adducts Mechanism Excision of damaged strand, resynthesis, and ligation Key Pathways GG-NER and TC-NER Core Enzymes TFIIH, XPC, CSA/CSB, XPF-ERCC1, XPG Clinical Disorders XP, CS, TTD
