Xeroderma pigmentosum (XP) is an inherited disorder in which defective nucleotide excision repair (NER) of UVR-induced DNA damage (largely cyclobutane pyrimidine dimers, CPDs) results in exaggerated sunburn, skin cancer and premature photoageing. XP is divided into seven complementation groups according to the defective protein component of the NER pathway. We aim to use this unique disease model to study the role of UVR-induced DNA damage and its repair in the pathogenesis of sunburn, skin cancer and photoageing, with significant implications for the general population. As part of the UK National XP Service, 70 patients have been carefully phenotyped. Although all patients were thought to have similar cutaneous features, we have recently discovered significant differences between complementation groups. Not all patients have exaggerated sunburn on minimal sun exposure and there are variations in skin cancer incidence. The rate and extent of UVR-induced CPD repair in XP dermal fibroblast cultures from all complementation groups will be assessed and correlated to the incidence of skin cancer in specific groups. This will not only add to our understanding of specific defects in NER but has significant prognostic value for XP patients, allowing personalisation of their management. Apoptosis and transcription arrest will be quantified following UVR exposure to look for a correlation with severe sunburn XP groups. This will improve our understanding of the mechanism for sunburn. To examine the role of defective CPD repair in the accelerated photoageing in XP, CPD repair and matrix metalloproteinase 1 (MMP-1) expression will be studied. An inverse relationship will support a role for CPDs as an initiator of photoageing in XP. By examining the cultured fibroblasts of patients across all complementation groups after UVR exposure, we aim to better understand the consequences of specific defects in the NER pathway and to improve the clinical care of XP patients.