© 2009 BMJ Publishing Group Ltd
A novel splice variant of the DNA-PKcs gene is associated with clinical and cellular radiosensitvity in a xeroderma pigmentosum patient.
1 Institute of Cancer Researh, Royal Marsden Hospital, Surrey, United Kingdom;
2 University College London Cancer Institute, United Kingdom;
3 University of Sussex, United Kingdom;
4 Bart's and the London Hospital, United Kingdom;
5 Brunel University, United Kingdom;
6 Brighton University, United Kingdom
Correspondence to: Christopher Noel Parris, Biosciences, Brunel University, Brunel University,, School of Health Sciences and Social Care, Division of Biosciences, Uxbridge, UB8 3PH, United Kingdom; christopher.parris{at}brunel.ac.uk
Accepted 10 September 2009
Background: Radiotherapy-induced DNA double strand breaks (DSB) are critical cytotoxic lesions. Inherited defects in DSB DNA repair pathways lead to hypersensitivity to ionising radiation, immunodeficiency and increased cancer incidence. A patient with xeroderma pigmentosum complementation group C, with a scalp angiosarcoma exhibited dramatic clinical radiosensitivity following radiotherapy, resulting in death. A fibroblast cell line from non-affected skin (XP14BRneo17) was hypersensitive to ionising radiation and defective in DNA double strand break repair.
Aim: To determine the genetic defect causing cellular radiation hypersensitivity in XP14BRneo17 cells.
Methods: Functional genetic complementation whereby copies of human chromosomes containing genes involved in DNA DSB repair (chromosomes 2, 5, 8 10, 13 and 22) were individually transferred to XP14BRneo17 cells in an attempt to correct the radiation hypersensitivity. Clonogenic survival assays and 
-H2AX immunofluorescence were conducted to measure radiation sensitivity and repair of DNA DSBs. DNA sequencing of defective DNA repair genes was performed.
Results: Transfer of chromosome 8 (location of DNA-PKcs gene), and transfection of a mammalian expression construct containing the DNA-PKcs cDNA restored normal ionising radiation sensitivity and repair of DNA DSBs in XP14BRneo17 cells. DNA sequencing of the DNA-PKcs coding region revealed a 249 bp deletion (between base pairs 3656-3904) encompassing exon 31 of the gene.
Conclusion: We provide evidence of a novel splice variant of the DNA-PKcs gene associated with radiosensitivity in a xeroderma pigmentosum patient and report the first double mutant in distinct DNA repair pathways being consistent with viability.
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