The genetic blueprint for every living cell, DNA, is under constant assault, comparable to an instruction manual susceptible to errors. To counteract this, cells have developed maintenance systems to safeguard their genetic information. One of these is Nucleotide Excision Repair (NER), a versatile system for fixing significant types of DNA damage. NER acts as a defense mechanism, ensuring the cell’s instruction manual remains clear and functional.
Triggers for Nucleotide Excision Repair
Nucleotide Excision Repair is activated by “bulky” DNA lesions that physically distort the double helix structure of the DNA molecule. This distortion interferes with processes like replication and transcription. The repair machinery recognizes these structural abnormalities rather than changes to individual chemical bases.
A primary trigger for NER is damage from ultraviolet (UV) radiation in sunlight. When UV light strikes DNA, it can cause adjacent pyrimidine bases—typically two thymines—to fuse together incorrectly, forming pyrimidine dimers. This fusion creates a rigid kink in the DNA strand, distorting the helix.
The system also responds to chemical adducts, which are molecules from external sources that improperly attach to the DNA. Carcinogens in tobacco smoke, for instance, can form bulky adducts when they bind to DNA bases. Similarly, exposure to certain industrial chemicals or chemotherapeutic drugs can lead to the formation of these structurally disruptive lesions.
The Step-by-Step Repair Mechanism
The process begins with damage recognition, where surveillance proteins patrol the genome scanning for structural distortions. When a bulky lesion, like a pyrimidine dimer, is identified, these proteins halt and flag the area. This action initiates the repair cascade.
Once the damage is located, the next step involves unwinding the DNA. A specialized set of proteins separates the two strands of the double helix around the lesion, creating a stable, open “bubble.” This action exposes the damaged segment and provides access for the repair machinery.
With the damaged strand isolated, proteins called endonucleases act as molecular scissors. These enzymes make two cuts into the backbone of the damaged strand, one on each side of the lesion. This dual-incision frees a short, single-stranded DNA segment, typically 24-32 nucleotides in length, which is then removed from the helix, leaving a gap.
Following the removal of the damaged segment, the gap is filled. An enzyme called DNA polymerase synthesizes a new, correct stretch of DNA using the opposite, undamaged strand as a template. This ensures the genetic information is restored with high fidelity.
The final step is ligation. After the DNA polymerase has filled the gap, a small nick remains in the backbone of the repaired strand. An enzyme known as DNA ligase seals this nick, creating a phosphodiester bond. This joins the newly synthesized DNA segment to the rest of the strand, completing the repair.
Consequences of a Faulty System
When the Nucleotide Excision Repair system is defective due to inherited genetic mutations, the consequences for human health can be significant. The inability to repair DNA damage effectively leads to a group of disorders characterized by sensitivity to DNA-damaging agents. These conditions highlight the work NER performs to protect the genome.
A well-known disease associated with NER defects is Xeroderma Pigmentosum (XP). Individuals with XP have an impaired ability to correct DNA damage induced by UV radiation. Because their cells cannot effectively remove the pyrimidine dimers caused by sunlight, even minimal sun exposure results in severe sunburns, freckle-like pigmentation, and premature aging of the skin.
The accumulation of unrepaired DNA damage in skin cells increases the risk of cancer. Patients with XP have a risk of developing skin cancer that is more than 1,000 times higher than that of the general population, often at a very young age. Beyond the skin, some forms of XP are also associated with neurological symptoms, as NER is needed to maintain DNA integrity in non-dividing cells like neurons.
Global Versus Targeted Repair Pathways
The cell employs a two-tiered strategy for Nucleotide Excision Repair to manage its resources. This involves two sub-pathways that differ in how they detect DNA damage: Global Genome NER (GG-NER) and Transcription-Coupled NER (TC-NER). This dual system allows the cell to prioritize the repair of its most active genes.
Global Genome NER acts as a broad surveillance system, scanning the entire genome for bulky lesions. This pathway is responsible for finding and fixing damage in both active and inactive regions of DNA, including silent genes and non-coding sequences.
In contrast, Transcription-Coupled NER is a high-priority pathway that focuses on damage within actively transcribed genes. When the cellular machinery (RNA polymerase) that reads a gene to produce a protein encounters a bulky lesion, it stalls. This stall acts as an urgent signal, recruiting specialized TC-NER proteins to the site to clear the obstruction quickly.