Nucleotide excision repair

Nucleotide excision repair (NER) is a DNA repair mechanism that is essential for maintaining the integrity of the genome. It is a versatile system that can recognize and repair a wide range of structurally unrelated DNA damage, including ultraviolet (UV) light-induced pyrimidine dimers and chemical carcinogen-induced bulky adducts.

Mechanism

NER operates through a cut-and-patch mechanism. It involves the following steps:

1. Damage recognition: The first step in NER is the recognition of DNA damage. This is achieved by a complex of proteins, including XPC (xeroderma pigmentosum complementation group C) and HR23B (RAD23 homolog B).
2. Excision: Once the damage is recognized, the DNA around the damage site is unwound and a single-stranded DNA segment containing the lesion is excised. This is carried out by the endonucleases XPF (xeroderma pigmentosum complementation group F) and ERCC1 (excision repair cross-complementation group 1).
3. Repair synthesis: The gap left by the excision is filled in by a DNA polymerase, which synthesizes new DNA using the undamaged strand as a template.
4. Ligation: Finally, the newly synthesized DNA is joined to the existing DNA by a DNA ligase.

Clinical significance

Defects in NER can lead to several human disorders, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). These disorders are characterized by sensitivity to UV light and a predisposition to skin cancer.

NER is also a target for cancer therapy. Many chemotherapeutic drugs work by inducing DNA damage that is recognized and repaired by NER. Inhibiting NER can therefore enhance the effectiveness of these drugs.

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