*2.1.2 Nucleotide excision repair (NER)*

NER is the primary pathway for repairing a wide range bulky DNA lesions, including UV-induced photoproducts (cyclopyrimidine dimers [CPDs], 6–4 photoproducts [6-4PPs]), adducts formed by mutagens in the environment such as benzo[a]pyrene or some aromatic amines, some oxidative endogenous lesions such as cyclopurines, and adducts formed by cancer chemotherapeutic drugs such as cisplatin. NER can be initiated by two subpathways: global genome NER (GG-NER) where the participation of XPC-RAD23B is involved and the transcription-coupled NER (TC-NER) where RNA polymerase interacts with CSA, CSB, and XAB2. Both converge to complete the excision process requiring the core NER factors RPA, XPA, TFIIH, XPD, XPB, XPG, and ERCC1–XPF, among other auxiliary proteins [47]. NER activity decreases with aging possibly because there is a transcriptional downregulation of NER genes together with an altered protein function or processing and a decrease in energy production [48]. In this manner, it was previously observed that aged human skin [49] and fibroblasts [50] showed decreased levels of XPB, PCNA, RPA, XPA, and p53, and more importantly the UVB-induced pyrimidine dimers were removed in a slower manner than in younger counterparts [50]. Interestingly, the effect of age on the repair of UV-induced DNA damage varies for transcribed and nontranscribed DNA, decreasing considerably in unexpressed DNA [51, 52] but improving in both cases under calorie restricted diets [52]. Furthermore, UV-induced damage and repair in telomeres showed to be slower and less frequent than in other regions of the genome such as active genes [53]. Additionally, ERCC1 and XPF, which are considered as the rate-limiting members in NER, also showed an age-dependent decline in their relative expression levels [54]. Because XPC, XPB, and XPF appear to be dependent on the activation status of the IGF-1R, decreased levels of IGF-1R observed with aging also contributed with the decline of NER pathway [55]. Meanwhile, in an assay based in plasmid reactivation after UV damage, cells from older donors introduced an increased number of mutations in the transfected plasmid, which suggests that not only the repair is less efficient with age but also more mistakes are made [51].
