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Nucleotide excision repair fixes bulky lesions caused by ultraviolet light and certain chemical carcinogens. These lesions distort the normal double helical structure of DNA, creating physical aberrations that can block DNA replication or transcription. If left unrepaired, this damage can accumulate and lead to mutations, cancer, or disease.

UvrA and UvrB proteins work together as a complex, traveling along the DNA strands to detect physical aberrations caused by lesions. Once they identify a damaged region, the enzyme complex signals for strand separation and excision of the affected area. This detection mechanism is the critical first step in nucleotide excision repair.

Endonuclease enzymes such as UvrC cleave the DNA strand on both sides of the damage site. This cutting action excises the damaged region from the DNA molecule. After excision, other enzymes fill and seal the gap to complete the repair process.

After endonuclease enzymes remove the damaged section, DNA polymerase fills the gap with new nucleotides that match the original sequence. DNA ligase then seals the edges between the newly synthesized DNA and the existing strand, restoring the DNA molecule to its original structure and function.

Mutations in the nucleotide excision repair pathway can cause severe diseases like xeroderma pigmentosum in humans. Affected individuals are highly sensitive to UV exposure, developing severe skin burns after brief sunlight exposure and showing a 2000-fold increase in skin cancer incidence. Without proper repair mechanisms, DNA damage accumulates, leading to premature aging, neurological abnormalities, and potentially cancerous tumors.

In prokaryotes, nucleotide excision repair relies on three Uvr proteins: UvrA, UvrB, and UvrC. Eukaryotes employ more than a dozen proteins to regulate the same repair process. Despite this complexity difference, both systems follow the same fundamental mechanism of detection, excision, and synthesis of new nucleotides.

Nucleotide excision repair prevents mutations by removing bulky lesions before they can be replicated or transcribed. UV radiation and chemical carcinogens regularly damage DNA, creating bends or kinks that block normal cellular processes. By repairing these lesions promptly, nucleotide excision repair protects cells from accumulating mutations that could cause cancer or disease.