Genomic DNA lesions processed by nucleotide excision repair (NER-processed DNA lesions)

Genomic DNA lesions processed by nucleotide excision repair (NER) are primarily bulky, helix-distorting modifications to the DNA structure, most notably cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) induced by ultraviolet (UV) radiation (Sancar, A. 2003. Chemical Reviews). These lesions occur when adjacent pyrimidine bases covalently bond, creating a physical block that stalls DNA polymerase and RNA polymerase, leading to mutations or cell death (Marteijn, J. A., et al. 2014. Nature Reviews Molecular Cell Biology). The NER pathway is the specialized cellular machinery responsible for identifying, excising, and repairing these specific types of damage to maintain genomic stability (Schärer, O. D. 2013. Cold Spring Harbor Perspectives in Biology). Deficiencies in the repair of these lesions are directly linked to severe genetic disorders such as Xeroderma pigmentosum, which is characterized by an extreme predisposition to skin cancers (DiGiovanna, J. J., & Kraemer, K. H. 2012. Journal of Investigative Dermatology). In a therapeutic context, these lesions are the focus of DNA repair-enhancing agents, such as topical liposomal T4 endonuclease V, which aims to accelerate the removal of CPDs to prevent skin cancer in high-risk individuals (Dremel, J., et al. 2001. The Lancet). Conversely, the NER pathway itself is sometimes targeted for inhibition to enhance the efficacy of DNA-damaging chemotherapeutic agents like cisplatin, which creates similar bulky adducts (Spivak, G. 2015. Archives of Toxicology).

Other names

Cyclobutane pyrimidine dimers6-4 photoproductsCPDs6-4PPsBulky DNA adductsUV-induced DNA damageHelix-distorting DNA lesions

Nucleotide excision repair (NER) involves the recognition of bulky DNA lesions by proteins like XPC or the RNA polymerase II complex, followed by dual incision of the damaged strand by XPF and XPG nucleases, removal of the damaged oligonucleotide, and gap-filling DNA synthesis by DNA polymerases (Marteijn, J. A., et al. 2014. Nature Reviews Molecular Cell Biology).