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

Lead Research Organisation: King's College London
Department Name: Genetics and Molecular Medicine


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.

Technical Summary

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.

Planned Impact

We believe that XP patients in the UK and the rest of the world will greatly benefit from our research. The UK National XP Service comprises a multidisciplinary team consisting of a number of specialties, including dermatology, ophthalmology, neurology, psychology and genetics. It is the only service that performs genotype-phenotype correlation within complementation groups. Our research will enable detailed phenotyping of individual patients and this will enhance our delivery of specific personalised advice to XP patients, with particular reference to sunburn susceptibility, skin cancer development and skin photoageing. The multidisciplinary composition of the XP service means that our results are more likely to inform different specialties. Benefits to patients are not likely to arise until quite late in the project; 2 years at the earliest, but will have a long duration.

XP is a model for the role of DNA photodamage in sunburn, skin cancer and probably photoageing. Mechanistic insights from this study will have wider implications for these common clinical outcomes, especially in normal sun-sensitive skin types who are prone to skin cancer. The increasing incidence of skin cancer in many countries, including the UK, presents large burdens on health services. One probable reason for this is the greater availability of cheap flights to sunny countries coupled with the intention to sunbathe without adequate photoprotection. It is therefore crucial to develop better strategies for photoprotection, which is a realistic way of reducing the health risks of solar exposure and quality of life/ self image by the reduction of photoageing. This can be done at two levels: public health campaigns by policy makers such as Cancer Research UK, Public Health England, the World Health Organization, and the skincare/ sunscreen industry. A more detailed understanding of the consequences of DNA damage is likely to spur the development of better approaches to photoprotection, including the development of agents that enhance DNA repair in the skin. These are present in sun care products in Europe but sold with very general claims based on little or no data. Industry is likely to be very interested in a relationship between DNA photodamage and photoageing, which is a deterministic consequence of solar exposure. This could eventually result in new products in an expanding market. From a public health point of view, fear of photoageing may be more useful than fear of skin cancer. Professor Young has established connections with public health bodies and the skincare industry and is in a position to keep them informed of relevant developments. Benefits to public health bodies and industry are unlikely to occur until after the end of the project.

The fellowship applicant will acquire considerable transferable skills during the 3-year lifetime of the project. The will include proficiency in written and oral communication, considerable technical and statistical and IT expertise and the ability to analyze and interpret data. The applicant will also interact with the XP support group that requires the distillation of complex scientific information into lay terms.


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Description British Society for Investigative Dermatology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact National meeting to discuss progress in skin research. I submitted an abstract pertaining to the laboratory work on MMP expression after UVR in XP and control fibroblasts. I have been invited to present a poster of my data at this meeting
Year(s) Of Engagement Activity 2018
Description Divisional Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact I was invited to give a talk at the Genetics and Molecular Medicine Divisional Seminar on 16th June 2015. The title was "DNA repair deficiencies and mechanisms of sunburn: Xeroderma pigmentosum as a model". I presented my work to date to other postgraduate students and their supervisors within the division. The purpose was to increase awareness of my PhD subject and to invite any constructive feedback and comments. The talk was very well received, the audience was engaged and asked relevant questions about the mechanisms of DNA repair and methods for my experiments.
Year(s) Of Engagement Activity 2015
Description Poster presentation at International conference on Xeroderma pigmentosum and related diseases conference 20- 22 March 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Abstract submitted in December 2018 to this international conference. Outcome: selected for poster presentation. Research about oxidative stress link to photoageing
Year(s) Of Engagement Activity 2019
Description Presentation at British Association of Dermatology 9th Annual Meeting- BADGEM 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact I gave a presentation entitled: "Xeroderma pigmentosum: Increasing awareness of the variation in presenting clinical features in order to avoid diagnostic delay and improve prognosis". I submitted an abstract which was accepted for oral presentation. I was given a 15 minute slot to present data which I had collected (as part of my MRC fellowship) on the time between presentation and diagnosis of XP in 70 patients. 58 patients (83%) presented to a health professional with a dermatological feature, eight patients (11%) presented with an ophthalmological feature, four patients (6%) presented with a neurological feature. Data analysis showed that from the age of presentation to confirmation of diagnosis there was an average time gap of 7.6 years with dermatological features, 11 years with ophthalmological features and 20.2 years with neurological features. Increasing awareness of the range of presenting XP clinical features among physicians will lead to an earlier confirmation of diagnosis and instigation of photoprotection, leading to improved prognosis in XP patients.
This talk stimulated debate on recognition of signs and symptoms of XP as well as increasing awareness of this rare disease
Year(s) Of Engagement Activity 2015