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Clinical and cellular ionizing radiation sensitivity in a patient with xeroderma pigmentosum

¹ Genome Damage & Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, , ² Radiotherapy/Clinical Oncology, St Bartholomew's Hospital, 25 Bartholomew Close, West Smithfield, London EC1A 7BE, , ³ Division of Biosciences, School of Health Sciences and Social Care, Brunel University, Kingston Lane, Uxbridge, Middlesex UP8 3PH, , ⁴ School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Lewes Road, Brighton BN2 4GJ, , ⁵ Institute of Environmental and Natural Sciences, Faraday Building, Lancaster University, Lancaster LA1 4YA, , ⁶ The Institute of Cancer Research, Royal Cancer Hospital, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK, , ⁷ INSERM U647, ID17, European Synchrotron Research Facility, Rue Jules Horowitz, BP220 – 38043 Grenoble, France,

XP14BR is a cell line derived from a xeroderma pigmentosum (XP) patient from complementation group C. The patient was unusual in presenting with an angiosarcoma of the scalp, treated by surgical excision and radiotherapy. Following 38 Gy in 19 fractions with 6 MEV electrons, a severe desquamation and necrosis of the underlying bone ensued, and death followed 4 years later. The cell line was correspondingly hypersensitive to the lethal effects of gamma irradiation. We had previously shown that this sensitivity could be discriminated from that seen in ataxia-telangiectasia (A-T). The cellular response to ultraviolet radiation below 280 nm (UVC) was characteristic of XP cells, indicating the second instance, in our experience, of dual cellular UVC and ionizing radiation hypersensitivity in XP. We then set out to evaluate any defects in repair of ionizing radiation damage and to verify any direct contribution of the XPC gene. The cells were defective in repair of a fraction of double strand breaks, with a pattern reminiscent of A-T. The cell line was immortalized with the vector pSV3neo and the XPC cDNA transfected in to correct the defect. The progeny derived from this transfection showed the presence of the XPC gene product, as measured by immunoblotting. A considerable restoration of normal UVC, but not ionizing radiation, sensitivity was observed amongst the clones. This differential correction of cellular sensitivity is strong evidence for the presence of a defective radiosensitivity gene, distinct from XPC, which is responsible for the clinical hypersensitivity to ionizing radiation. It is important to resolve how widespread ionizing radiation sensitivity is amongst XP patients.