Nucleotide Excision Repair (NER)

Nucleotide Excision Repair (NER) is a 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.

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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 prevention, and cell survival.

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Steps in NER (Generalized):

1. 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.
2. DNA Unwinding:
   • TFIIH complex (includes XPB and XPD helicases) unwinds the DNA around the lesion to form a bubble.
3. Excision of Damaged Strand:
   • Endonucleases (e.g., XPF-ERCC1 and XPG) cut the damaged strand on both sides of the lesion (~24–32 nucleotides).
4. DNA Synthesis:
   • DNA polymerase fills in the gap using the complementary strand as a template.
5. Ligation:
   • DNA ligase seals the final phosphodiester bond, restoring the DNA backbone.

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Key Proteins in NER (Human):

Protein/Complex	Role
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

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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

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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

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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