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Nucleotide excision repair fixes bulky DNA lesions caused by UV radiation and chemical carcinogens, such as pyrimidine dimers. These lesions distort the DNA helix and interfere with DNA replication and transcription. If left unrepaired, they can cause mutations leading to cancer or disease depending on which DNA sequences are disrupted.

In E. coli, UvrA and UvrB form a complex that scans genomic DNA for structural lesions. When the complex encounters a lesion, UvrA dissociates and UvrB binds tightly to the distorted DNA region. This recognition of physical aberrations allows the repair machinery to flag the damaged area for removal and repair.

UvrC is an endonuclease recruited by DNA-bound UvrB that makes incisions on either side of the lesion. These cuts allow the damaged DNA fragment to be excised from the strand. Following excision, DNA polymerase fills the gap with new complementary nucleotides, and DNA ligase seals the repair.

Transcription-coupled NER is initiated when an actively transcribing RNA polymerase encounters a bulky lesion and directly recruits UvrB to the damage site. This alternative pathway proceeds identically to regular NER but is triggered by transcription blockage rather than routine DNA scanning, allowing repair and transcription to resume.

Unlike prokaryotes, which use three proteins—UvrA, UvrB, and UvrC—eukaryotes employ more than a dozen proteins to regulate nucleotide excision repair. This increased complexity reflects the greater size and organization of eukaryotic genomes and the need for more sophisticated damage recognition and coordination mechanisms.

Mutations in the NER pathway cause diseases such as Xeroderma pigmentosum, associated with a 2000-fold increase in skin cancer incidence. XP patients are highly sensitive to UV exposure, developing severe burns after brief sunlight exposure, and often show premature aging and neurological abnormalities. Without functional repair, DNA damage accumulates, leading to abnormal cell death or cancerous tumors.

After DNA polymerase fills the gap with new complementary nucleotides, the enzyme DNA ligase seals the gap between the new and old DNA strands. This ligation completes the nucleotide excision repair process and restores the integrity of the DNA molecule.