Nucleotide excision repair

Overview

Nucleotide excision repair (NER) is a DNA repair mechanism that is essential for maintaining the integrity of the genome. It is a highly conserved process that is found in all domains of life, from bacteria to humansDNA Repair. NER is responsible for the removal of a wide range of DNA lesions, including those caused by ultraviolet (UV) light, chemical mutagens, and certain types of chemotherapy drugs. The importance of NER is underscored by the fact that defects in this pathway can lead to several human diseases, including xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD)Xeroderma Pigmentosum Cockayne Syndrome Trichothiodystrophy.

A microscopic view of a DNA strand undergoing nucleotide excision repair.

Mechanism of Nucleotide Excision Repair

The NER process involves several steps, each of which is carried out by a specific set of proteins. These steps include damage recognition, helix unwinding, damage excision, repair synthesis, and ligation. The process can be broadly divided into two sub-pathways: global genome NER (GG-NER) and transcription-coupled NER (TC-NER)DNA Repair Proteins.

Damage Recognition

The first step in NER is the recognition of DNA damage. In GG-NER, the XPC-RAD23B-CETN2 complex is responsible for detecting a wide range of helix-distorting lesions. In TC-NER, the damage is recognized by the stalling of RNA polymerase II at the lesion siteXPC Protein RNA Polymerase II.

A close-up view of the XPC-RAD23B-CETN2 complex recognizing DNA damage.

Helix Unwinding

Once the damage is recognized, the DNA helix around the lesion is unwound by the TFIIH complex, which contains the XPB and XPD helicasesTFIIH.

Damage Excision

The unwinding of the DNA helix allows the XPG and XPF-ERCC1 endonucleases to incise the damaged DNA strand on either side of the lesion, resulting in the excision of a single-stranded DNA fragment containing the lesionXPG XPF-ERCC1.

A detailed view of the XPG and XPF-ERCC1 endonucleases incising the damaged DNA strand.

Repair Synthesis

Following the excision of the damaged DNA, the resulting gap is filled in by DNA polymerase δ or ε, using the undamaged strand as a templateDNA Polymerase δ DNA Polymerase ε.

Ligation

The final step in NER is the sealing of the nick left by the repair synthesis. This is carried out by DNA ligase I or III, which forms a phosphodiester bond between the 3' hydroxyl end of the newly synthesized DNA and the 5' phosphate end of the adjacent undamaged DNADNA Ligase I DNA Ligase III.

A microscopic view of DNA ligase I or III sealing the nick left by the repair synthesis.

Diseases Associated with Nucleotide Excision Repair Defects

Defects in NER can lead to several human diseases, including XP, CS, and TTD. These diseases are characterized by a high sensitivity to UV light and a predisposition to skin cancer. In addition, patients with CS and TTD often exhibit neurological abnormalities and developmental defects.

Xeroderma Pigmentosum

XP is a rare genetic disorder characterized by extreme sensitivity to sunlight, resulting in a high risk of skin cancer. It is caused by mutations in any of the eight genes involved in NER (XPA through XPG and XPV)Xeroderma Pigmentosum.

Cockayne Syndrome

CS is a rare genetic disorder characterized by growth failure, neurological abnormalities, and premature aging. It is caused by mutations in the CSA or CSB genes, which are involved in TC-NERCockayne Syndrome.

Trichothiodystrophy

TTD is a rare genetic disorder characterized by brittle hair and nails, intellectual disability, and physical abnormalities. It is caused by mutations in the XPB, XPD, or TTDA genes, which are part of the TFIIH complex involved in NERTrichothiodystrophy.

A view of a DNA strand with a mutation leading to a nucleotide excision repair defect.

Conclusion

Nucleotide excision repair is a crucial DNA repair mechanism that maintains the integrity of the genome. Understanding the intricacies of this process can provide insights into the molecular basis of several human diseases and may lead to the development of novel therapeutic strategies.

References

^[1] ^[2] ^[3]

↑ 1. Scharer, O. D. (2013). Nucleotide excision repair in eukaryotes. Cold Spring Harbor perspectives in biology, 5(10), a012609. https://doi.org/10.1101/cshperspect.a012609
↑ 2. Marteijn, J. A., Lans, H., Vermeulen, W., & Hoeijmakers, J. H. (2014). Understanding nucleotide excision repair and its roles in cancer and ageing. Nature reviews. Molecular cell biology, 15(7), 465–481. https://doi.org/10.1038/nrm3822
↑ 3. Spivak, G. (2015). Nucleotide excision repair in humans. DNA repair, 36, 13–18. https://doi.org/10.1016/j.dnarep.2015.09.003

[1] 1. Scharer, O. D. (2013). Nucleotide excision repair in eukaryotes. Cold Spring Harbor perspectives in biology, 5(10), a012609. https://doi.org/10.1101/cshperspect.a012609

[2] 2. Marteijn, J. A., Lans, H., Vermeulen, W., & Hoeijmakers, J. H. (2014). Understanding nucleotide excision repair and its roles in cancer and ageing. Nature reviews. Molecular cell biology, 15(7), 465–481. https://doi.org/10.1038/nrm3822

[3] 3. Spivak, G. (2015). Nucleotide excision repair in humans. DNA repair, 36, 13–18. https://doi.org/10.1016/j.dnarep.2015.09.003

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