Please use this identifier to cite or link to this item: http://bura.brunel.ac.uk/handle/2438/3898
Title: A novel splice variant of the DNA-PKcs gene is associated with clinical and cellular radiosensitvity in a xeroderma pigmentosum patient
Authors: Abbaszadeh, F
Clingen, PH
Arlett, CF
Plowman, PN
Bourton, EC
Themis, M
Makarov, EM
Newbold, RF
Green, MHL
Parris, CN
Keywords: Functional complementation;Radiosensitivity;DNA repair;DNA-PKcs gene;Pre-mRNA
Issue Date: 2009
Publisher: MBJ
Citation: Journal of Medical Genetics. 46(11): 1-24
Abstract: 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 γ-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.
URI: http://jmg.bmj.com/content/early/2009/10/01/jmg.2009.068866.abstract?sid=bbe12cac-a832-43a1-865d-1bb6d9716b7e
http://bura.brunel.ac.uk/handle/2438/3898
ISSN: 1468-6244
Appears in Collections:Biological Sciences
Community Health and Public Health
Brunel OA Publishing Fund
Dept of Life Sciences Research Papers

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