Nucleotide excision repair (NER) is a damage repair mechanism that overhauls damage to one strand of the DNA through distorting the DNA helix. A single-stranded gap is generated by cleaving the damaged site, while the undamaged strand is copied to restore the intact helix for repair (nature.com, 2018). Typically, the cause of damage to the DNA is ultraviolet (UV) irradiation, environmental carcinogens or chemical compounds. These negative factors can lead to hereditary defects in the NER pathway and are linked to genetic diseases such as xeroderma pigmentosum (XP) and other forms of cancer and neurodegenerative diseases.
However, nucleotide excision repair is a highly effective damage repair mechanism due to its level of flexibility compared to other DNA repair systems. It recognizes damaged areas by detecting abnormal structure and abnormal chemistry. Many biochemical and genetic studies have been conducted to understand the fundamentals of NER (Kowaiski, 2018).
Nucleotide excision repair utilizes two subpathways—the global genome repair (GG-NER) and the transcription-coupled (TC-NER) pathways—the names of which are derived from their distinct temporal roles during the cell cycle. GG-NER is processed during all phases of the cell cycle. It repairs damages on active genes at both DNA strands (transcribed and non-transcribed). “In GGR-NER the first step of damage recognition involves XPC-hHR23B complex together with XPE complex (in prokaryotes, uvrAB complex)” (www.genome.jp, 2015). TC-NER is processed when an active transcription site is blocked which interrupts an RNA polymerase in the activity of elongation (Kelly & Fishel, 2016). “TCR refers to the expedited repair of lesions located in the actively transcribed strand of genes by RNA polymerase II (RNAP II)” (www.genome.jp, 2015).
Furthermore, scientists Kelly and Fishel describe the process of nucleotide excision repair in the following steps:
1. DNA damage recognition
2. Assemble a repair (multi-protein) complex
3. Unwind the section of dsDNA
4. Bind the repair complex to the damaged site
5. Perform double incision of the damaged strand with excision activities
6. Remove the damage-containing oligonucleotide
7. Synthesize new nucleotides using the undamaged DNA strand
8. Ligate the repaired section of DNA
Nucleotide excision repair (NER) uses a “cut and patch” approach to eliminating and removing various bulky DNA lesions typically caused by UV irradiation, environmental mutagens, and specific chemotherapeutic agents. “The global genome NER (GG-NER) subpathway prevents mutagenesis by probing the genome for helix-distorting lesions, whereas transcription-coupled NER (TC-NER) removes transcription-blocking lesions to permit unperturbed gene expression, thereby preventing cell death” (Marteijn, Lans, Vermeulen, & Hoeijmakers, 2014). As a result, inhibited GG-NER pathways often lead to a susceptibility to cancer and other malignancies; while similarly, defective TC-NER mechanisms are the genesis for a wide-range of ranging from extreme sensitivity to ultraviolet light seen in xeroderma pigmentosum (XP) to severe, accelerated aging conditions, such as Cockayne Syndrome.
Xeroderma pigmentosum (XP) is a rare skin disease and a person with this disorder usually tells that they are allergic to the sunlight. XP is not an allergy to the sun, however, is a hereditary condition where a person is very sensitive to sunlight due to a defect in the person’s DNA repair system. XP is a rare genetic disorder in which the DNA repair pathways cannot fix the damage to DNA caused by exposure to ultraviolet (UV) rays from sunlight. XP patients suffer from extreme ocular and dermal sensitivity to sun exposure that leads to cutaneous atrophy, cutaneous telangiectasia, and early onset of malignant melanoma (Nouspikel, 2008).
The cause of XP is due to a person inheriting one recessive XP gene from each parent. XP can occur in all races and in both sexes. There are usually total three stages of XP. The first stage starts around 6 months after birth. The symptom is characterized by reddening of the skin with scaling and freckles starting around the face and moving to the neck and lower legs. The symptoms of the second stage are irregular patches of lightened, darkened skin, and blood vessels and veins can be visualized and shown through the skin as the skin becomes thinner. The third stage is the development of skin cancers and aesthetic keratosis which is an early form of squamous cell carcinoma.
Individuals with this disorder do not have the proper endonucleases or proteins necessary to repair this lesion damage. If they are exposed to UV light those thymine dimers cannot easily be repaired. Within the XP disorder, certain proteins are necessary for DNA repair. Damaged regions are recognized by proteins and other proteins help unwind DNA to excision the damaged region (NIH U.S National Library of Medicine, 2018). Once the damage is removed DNA polymerase repairs the DNA, the cause of XP is a mutation in the gene known as XPA, which is required to make repairs to the damaged DNA. XPA encodes a protein that is recruited by XPC and R23, which are the proteins that recognized damaged DNA. Then, XPA recruits ERCC1 and XPF, so that they can excise the damage lesion (Figure 1). The damaged DNA will lead to possible Basal Cell Carcinoma and other epidermal malignancies (NIH U.S National Library of Medicine, 2018).