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Title: An investigation of cellular radiosensitivity associated with immunodeficiency
Author: Evans, Paul Michael
ISNI:       0000 0001 3453 9387
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2005
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DNA Double Strand Breaks (DSBs) are induced by ionising radiation, but also arise during normal physiological processes such as V(D)J recombination during lymphocyte development. The induction of DSBs leads to the activation of proteins involved in DNA repair, but also initiates p53 dependent pathways that can result in cell cycle arrest and/or apoptosis. Defects in this damage response network may therefore result in immunodeficiency and cellular radiosensitivity. Skin biopsies obtained from undefined immunodeficient patients were used to generate primary fibroblast lines, and a group of these demonstrated cellular radiosensitivity using fibroblast survival assays. Whilst radiation-induced lymphocyte apoptosis was found to be an unreliable measure of intrinsic radiosensitivity, the examination of fibroblast division early after irradiation determined that radiosensitive fibroblasts undergo distinct cell fates after irradiation. Further characterisation revealed that all the identified radiosensitive lines were able to initiate p53-dependent gene transcription after irradiation. Analysis suggested that one undefined line (F96) might harbour a defect in DSB repair. Sequence examination of F96 candidate genes confirmed the presence of 2 novel mutations in the Artemis DNA repair gene that were expressed from separate alleles. Cloning of the Artemis gene also allowed the discovery of a new alternative exon and many novel splice variants. Concurrently, the F96 line was found to induce abnormally high levels of p53 activation after irradiation, which was associated with a more widespread induction of p53 target genes. This indicated that after DNA damage, defects in DSB repair might combine with other genetic factors that impair cellular survival to confer a radiosensitive immunodeficient phenotype.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available