Xeroderma pigmentosum: a model to study molecular, cellular and clinical consequences of specific defects in the nucleotide excision repair pathway

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Xeroderma pigmentosum (XP) is a rare inherited disorder affecting a patient's ability to go outside during daylight, as they cannot repair skin damage caused by the sun's ultraviolet rays (UVR). XP patients are reported to suffer severe sunburn, even on cloudy days. They also develop premature ageing of their skin and have a 10,000-fold increase risk of getting skin cancers. For this reason all XP patients are advised to sun protect by wearing thick clothes, socially unacceptable facial visors and lots of sunscreen. This is really difficult and has a huge impact on their lives.The skin changes in XP are caused by the damage to the DNA inside skin cells after exposure to UVR. XP patients fall into seven separate groups (A to G) according to the part of the skin damage repair machinery that is not working properly. In people without XP this is rapidly repaired. In XP patients the DNA damage is not completely repaired. If the DNA damage is severe it causes skin cells to die and this leads to sunburn. Sometimes the damage remains in the skin cells as they continue to grow and divide. It is this same DNA damage which causes the formation of skin cancers, explaining the significant increased risk of skin cancer in XP. Patients also show signs of premature skin ageing. It is known that DNA damage caused by UVR increases the breakdown of a protein called collagen in the skin. Collagen is important to keep the skin looking young. In XP patients DNA damage is not fully repaired and more collagen is broken down, causing premature ageing. Until recently it was thought that all XP patients show the same changes on their skin (extreme sunburn, premature ageing and lots of skin cancers); however, this is not the case. As part of the specialised UK National XP Hospital Clinic we have been able to carefully look at 70 patients with this rare disease. This UK Clinic is the largest of its kind looking after XP patients in the world. All our patients have given their permission for us to use the information collected about them. We have recently shown that not all XP patients suffer extreme sunburn (only patients in groups A, B, D, F, and G). Also the risk of getting a skin cancer is different between groups. This is information is new and very important for this research.In order to diagnose XP, all patients seen in the National Clinic have had a skin biopsy. These patients have all given us permission to use their skin biopsy in our research. In the laboratory we can grow cells from the skin biopsy in a thin layer. We plan to expose these patient skin cells to UVR produced by a machine in the laboratory. We will perform experiments to see how much DNA damage remains after the XP cells have been exposed to UVR. It would be interesting to see if the differences in the DNA damage in XP groups relate to the risk of developing skin cancers. This information could help us better advise and look after our patients, particularly in relation to sun protection. Similarly we will also look at reasons behind variability in sunburn between different XP groups. Finally we will measure the levels of certain enzymes in the skin known to be involved in skin ageing to see if there are higher levels in the skin cells of XP patients when compared to non-XP patients after UVR. This may give rise to more research into how the skin ages and what could be done to prevent it.By studying this rare disease we hope to increase our understanding of how UVR and DNA damage in XP patients causes sunburn, skin cancers and skin ageing and why there are differences in different XP groups. This research will help shed light on the machinery involved in repair of DNA damage caused by UVR and more importantly it will improve the clinical care of XP patient. Studying the mechanism for sunburn, skin cancers and skin ageing in XP also has major implications for the general population, particularly for skin cancer which is common and its incidence is increasing.