Document Type

Theses, Ph.D

Rights

This item is available under a Creative Commons License for non-commercial use only

Publication Details

Successfully submitted for the award of Doctor of Philosophy (Ph.D) to the Dublin Institute of Technology 2007.

Abstract

The main aim of the project is to investigate the role of the telomere/telomerase system in the bystander effect. Pilot experiments were carried out on broad field X-ray and y-ray-induced bystander effect in normal BJ and immortalized BJ1-hTERT human foreskin fibroblasts. This work led to finding increased clonogenic inactivation and chromosomal damage in cells directly hit by ionizing radiation and provided direct evidence for medium-mediated bystander responses (micronuclei and cell inactivation) in fibroblasts irradiated with low LET radiation. Later, this work on targeted and non-targeted effects of radiation was extended as a number of different responses appeared which suggested expanding the scope of the studies. Therefore different cytogenetic responses and their relationship were studies. Connections between bystander effects and other non-targeted effects of radiation, such as low-dose hypersensitivity/increased radio-resistance phenomenon were considered. There was an indication that the bystander effect may play a role in cell inactivation at low radiation doses. Formation of DSBs induces the phosphorylation of the tumor suppressor protein, histone H2AX and this phosphorylated form, named y-H2AX, forms foci at DSB sites. Although y-H2AX foci were observed in exponentially growing cells containing media conditioned on X-irradiated cells, it is not clear if X-irradiation leads to double strand breaks in bystander cells. The data in this study suggests that lesions other than DNA double strand breaks are involved in the bystander effect and that different mechanisms are responsible for the production of y-H2AX foci in direct irradiated and bystander cells. No induction of foci of y-H2AX in bystander confluent cells were observed and this result is discussed. Our findings rule out any major involvement of the telomerase in the bystander effect and propose that telomerase may have other physiological functions associated with the protection of chromosomes from breakage.

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