Deoxyribose nucleic acid, more commonly known as DNA, is the genetic material in human cells. The integrity of the nucleotides, or bases, that make up the sequence is important for proper cell function. Mutations to the chemical structure of the bases, caused by a number of environmental factors like ionizing radiation and chemical carcinogens, are corrected by a number of mechanisms built into the cell. One such process is nucleotide excision repair.
How Nucleotide Excision Repair Works
Nucleotide excision repair (NER) is a mechanism of repairing DNA damage by removing a patch of nucleotides that includes the DNA lesion, the damaged base or bases.
There are five steps in the NER process. First, the lesion is recognized and incisions made on both sides of the lesion on the damaged strand after the DNA strands are unwound and opened up, as they are during transcription and replication. Nucleotide excision repair proceeds rapidly in cells actively undergoing transcription and has been found linked to RNA polymerase II, the enzyme that builds the RNA strand during transcription. The association indicates the potential for correction as the transcription machinery notices chemically altered bases due to binding issues. In this context, NER allows transcription to correct the code before mutations occur.
In the third and fourth steps of NER, the damaged nucleotide(s) is removed and a patch is synthesized using DNA polymerase and the replication machinery. The other strand serves as a template for the missing nucleotides. Finally, DNA ligase seals off any remaining cut by the process called ligation.
Things That Can Go Awry With NER
If the NER process is halted in the middle, due to gene or protein dysfunction, a strand break occurs. The entire nucleotide excision process requires approximately 20 genes, several of which are associated with diseases like cancer. When the DNA is not repaired, the aberrant cell functioning, including aberrant transcriptional products, can cause disease.
Excess sun exposure is thought to overwhelm the process and result in some damage being left unrepaired in skin cells. Skin cancer is a common result of this damage. A disorder that increases the risk of skin cancer upon sun exposure is the autosomal recessive disorder xeroderma pigmentosum (XP). The disorder is named after the defective genes that cause it, at least five important gene in the NER mechanism, guiding the recognition, nicking, and excision process. UVB rays (sun exposure) have been shown to cause the formation of pyrimidine dimmers in the DNA, which are removed via nucleotide excision repair. Disrupting this process by mutating the XP genes is what causes the vulnerability to the cancer.
Additional source:
Cotran, Kumar, Collins. Robbins’ Pathologic Basis of Disease. Sixth Edition.
