NUCLEOTIDE EXCISION REPAIR AND ITS CONNECTION WITH CANCER AND AGEING

The intricacies of the GG-NER, TC-NER and presumably the broader TCR reaction combined with the occurrence of functions beyond repair of several of the NER factors and global genome repair defects translates into a complex and highly pleiotropic set of syndromes. However, by careful analysis of patients and mouse mutants we can come to the following simplifications. A defect in the global genome subpathway of NER, as observed in XPC patients, causes the cutaneous features of XP with the high incidence of skin cancer in the UV-exposed parts of the skin. When, in addition, the TC-NER pathway is affected, as in the case of XPA, the additional feature of accelerated neurodegeneration may be occurring as seen to an extreme extent in the DeSanctis-Cacchione form of XP. The CS features, including those apparent in TTD, may be the consequence of a defect in the broader TCR system, with TTD having on top of this the TFIIH instability leading to the typical brittle (unfinished) hair, nails and skin. This discloses some of the mechanistic intricacies that still need to be resolved. The problems caused by defective TCR can be further aggravated by a combination with a deficiency of the GG-NER subpathway, presumably because this increases the overall damage load. This may explain the very severe phenotype exhibited by some XPCS patients. Altogether this highlights the importance of the process that keeps our transcription going despite the continuous induction of DNA lesions: transcription-coupled repair.