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

着色性干皮病（XP）是一种罕见的遗传性疾病，影响患者在日光下外出的能力，因为他们无法修复太阳紫外线（UVR）造成的皮肤损伤。据报道，XP患者即使在阴天也会遭受严重的晒伤。他们的皮肤也会过早老化，患皮肤癌的风险会增加10,000倍。出于这个原因，所有XP患者都被建议穿厚衣服，戴社会上不可接受的面部遮阳板和大量的防晒霜来防晒。这真的很难，对他们的生活影响巨大，XP中的皮肤变化是由于暴露在紫外线下后皮肤细胞内部的DNA受损而引起的。XP患者分为七个独立的组（A至G）根据皮肤损伤修复机器的部分，不能正常工作。在没有XP的人，这是迅速修复。在XP患者中，DNA损伤没有完全修复。如果DNA损伤严重，会导致皮肤细胞死亡，从而导致晒伤。有时，损伤仍然存在于皮肤细胞中，因为它们继续生长和分裂。正是这种DNA损伤导致皮肤癌的形成，解释了XP中皮肤癌风险的显着增加。患者也会出现皮肤过早老化的迹象。众所周知，紫外线辐射造成的DNA损伤会增加皮肤中一种叫做胶原蛋白的蛋白质的分解。胶原蛋白对保持皮肤年轻很重要。在XP患者中，DNA损伤没有完全修复，更多的胶原蛋白被分解，导致过早衰老。直到最近，人们还认为所有XP患者的皮肤都显示出相同的变化（极度晒伤，过早衰老和许多皮肤癌）;然而，事实并非如此。作为专业的英国国家XP医院诊所的一部分，我们已经能够仔细观察70名患有这种罕见疾病的患者。这个英国诊所是世界上最大的照顾XP患者的诊所。我们所有的患者都允许我们使用收集到的关于他们的信息。我们最近的研究表明，并非所有XP患者都遭受严重晒伤（仅A、B、D、F和G组患者）。此外，患皮肤癌的风险在不同群体之间是不同的。这是新的信息，对这项研究非常重要。为了诊断XP，所有在国家诊所看到的患者都进行了皮肤活检。这些患者都允许我们在研究中使用他们的皮肤活检。在实验室里，我们可以从皮肤活检中培养出薄层细胞。我们计划将这些患者的皮肤细胞暴露在实验室机器产生的紫外线下。我们将进行实验，看看XP细胞暴露在紫外线辐射下后，还有多少DNA损伤。看看XP组中DNA损伤的差异是否与患皮肤癌的风险有关，这将是一件有趣的事情。这些信息可以帮助我们更好地建议和照顾我们的病人，特别是在防晒方面。同样地，我们也将研究不同XP组之间晒伤差异的原因。最后，我们将测量皮肤中已知与皮肤老化有关的某些酶的水平，以确定在紫外线照射后，XP患者的皮肤细胞中是否有比非XP患者更高的水平。这可能会引发更多关于皮肤如何老化以及如何预防的研究。通过研究这种罕见的疾病，我们希望增加我们对紫外线和DNA损伤如何导致XP患者晒伤，皮肤癌和皮肤老化以及为什么不同XP组之间存在差异的理解。这项研究将有助于阐明参与UVR引起的DNA损伤修复的机制，更重要的是，它将改善XP患者的临床护理。研究XP中晒伤、皮肤癌和皮肤老化的机制对普通人群也有重要意义，特别是对于常见的皮肤癌，其发病率正在增加。

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.