Nucleotide Excision Repair Only Repairs Pyrimidine Dimers

Nucleotide Excision Repair: Beyond Pyrimidine Dimers

The statement "Nucleotide Excision Repair (NER) only repairs pyrimidine dimers" is an oversimplification. While NER is highly efficient at repairing pyrimidine dimers, particularly cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), formed by ultraviolet (UV) radiation, its role extends far beyond these specific lesions. NER is a crucial DNA repair pathway responsible for removing a wide array of bulky DNA lesions that distort the DNA double helix. These lesions can be caused by various endogenous and exogenous factors, including UV radiation, certain chemicals, and oxidative stress. This article will delve into the complexities of NER, exploring its mechanisms, the types of damage it repairs, and the consequences of its malfunction.

Understanding the NER Mechanism: A Multi-Step Process

NER is a highly conserved and complex process involving a series of intricate steps. Its versatility stems from its ability to recognize and remove a wide range of structurally diverse DNA lesions. The process can be broadly categorized into the following stages:

1. Damage Recognition: Spotting the Problem

The initial step in NER involves the recognition of the DNA lesion. This is where the pathway's versatility is evident. Different sub-pathways exist, each tailored to specific types of damage.

• Global Genome NER (GG-NER): This pathway is responsible for repairing lesions throughout the genome. It relies on damage recognition factors like XPC in eukaryotes and UvrA/UvrB in bacteria. These proteins scan the DNA, detecting distortions in the helix caused by bulky adducts. The XPC complex is particularly adept at recognizing lesions that induce a large helix distortion.

• Transcription-Coupled NER (TC-NER): This pathway prioritizes the repair of lesions that block RNA polymerase II transcription. When RNA polymerase stalls at a lesion, it recruits factors like CSA and CSB (in eukaryotes), leading to the subsequent repair steps. This pathway ensures the rapid repair of lesions in actively transcribed genes, protecting crucial cellular processes.

2. DNA unwinding: Exposing the Damage

Once a lesion is identified, the DNA helix around the damaged site needs to be unwound to provide access to the repair machinery. Helicases, such as TFIIH (in eukaryotes) and UvrB (in bacteria) play a vital role in unwinding the DNA around the lesion, creating a single-stranded DNA bubble that encompasses the damage.

3. Incision: Cutting Out the Damage

After unwinding, the damaged strand is incised on either side of the lesion by endonucleases. In eukaryotes, XPF/ERCC1 and XPG endonucleases make these incisions, while in bacteria, UvrC makes the incisions. These incisions create a gap in the DNA strand containing the damaged nucleotide(s).

4. DNA Synthesis: Filling the Gap

Once the damaged segment is removed, DNA polymerase fills in the gap using the undamaged strand as a template. This process ensures that the correct nucleotide sequence is restored.

5. Ligation: Sealing the Deal

Finally, DNA ligase seals the nick, completing the repair process and restoring the integrity of the DNA double helix.

Beyond Pyrimidine Dimers: The Broad Spectrum of NER substrates

While pyrimidine dimers are frequently cited as the primary substrate for NER, a vast array of other DNA lesions are also repaired by this pathway. These include:

• Bulky DNA adducts: These are formed by the covalent attachment of large chemical groups to DNA bases, often induced by exposure to environmental carcinogens like polycyclic aromatic hydrocarbons (PAHs) and aflatoxins. These adducts can significantly distort the DNA helix, making them targets for NER.

• Interstrand crosslinks (ICLs): ICLs are covalent bonds that link the two strands of DNA, hindering replication and transcription. Although NER doesn't fully resolve ICLs on its own, it plays a crucial role in the initial processing of these lesions, preparing them for other repair pathways like Fanconi anemia pathway.

• DNA damage from oxidative stress: Reactive oxygen species (ROS) generated during normal metabolism or by exposure to environmental factors can cause various types of DNA damage, including base modifications (e.g., 8-oxoguanine) and single-strand breaks. Some of these oxidized bases cause significant DNA helix distortion, thus triggering the NER pathway.

• Intrastrand crosslinks: Unlike interstrand crosslinks, these link two bases on the same DNA strand, distorting the helix and triggering the NER response.

The Consequences of NER Deficiency

Defects in the NER pathway can lead to severe consequences, highlighting its critical role in maintaining genome stability. The most striking example is xeroderma pigmentosum (XP), a rare genetic disorder characterized by extreme sensitivity to sunlight and a drastically increased risk of skin cancer. XP is caused by mutations in genes encoding various NER proteins. Individuals with XP cannot efficiently repair UV-induced DNA damage, leading to an accumulation of mutations that can ultimately drive cancer development.

Other NER-related disorders include:

• Cockayne syndrome (CS): A condition characterized by growth retardation, neurological abnormalities, and premature aging. CS involves defects primarily in TC-NER, suggesting that impaired repair of transcription-blocking lesions has severe developmental consequences.

• Trichothiodystrophy (TTD): This disorder is characterized by brittle hair, intellectual disability, and increased susceptibility to infections. TTD is often associated with defects in TFIIH, a crucial component of both GG-NER and TC-NER, emphasizing the importance of this complex in the repair of different types of lesions.

NER: A Versatile and Essential Repair Pathway

In conclusion, while NER is indeed highly proficient at repairing pyrimidine dimers, its role extends far beyond these specific lesions. Its ability to recognize and remove a wide range of bulky DNA adducts and helix-distorting damage makes it a crucial component of the cellular defense mechanism against genotoxic stress. The severity of the consequences observed in NER-deficient individuals underscores the paramount importance of this intricate repair pathway in maintaining genomic integrity and preventing disease. Its complexity and versatility are a testament to the cell's remarkable capacity to safeguard its genetic information against a multitude of threats. Further research into the nuances of NER continues to unravel its intricate mechanisms and broaden our understanding of its critical role in human health. The ongoing exploration of NER's intricacies promises to yield valuable insights into disease prevention and treatment strategies.