Cell-type-specific responses to DNA damage from acute and chronic radiation
type: CreativeWork
description: It is well understood that radiation causes damage to DNA, which triggers a DNA-damage response often centred on the signalling pathways of ATM, with the subsequent involvement of proteins such as p53, p21 and H2AX. Many experiments have been performed with cell lines derived from different origins and donors which, while invaluable for studying specific effects, restrict direct assessment of response variability between different cells, tissues and individuals. This thesis investigates normal tissue responses to DNA damage from acute and chronic radiation, including exploration of cell-type and individual-specific differences in DNA-damage response. Due to the difficulty of obtaining different primary cell types of isogenic background (necessary to prevent confounding results by inter-individual variation), there are still unanswered questions regarding the extent and details of cell-type-specific responses to ionising radiation. I have developed a method for isolation of primary cells from human tissue and compared cellular outcomes and molecular signalling in response to an X-ray dose. Using these primary cells, I show that cell type causes far more variability in radiation response, with keratinocytes, which have highest p21 protein levels, being most susceptible to cell cycle arrest and senescence, while donor variability is limited. Another issue that has received insufficient attention is the biological effects of chronic radiation. Both experimental and epidemiological evidence highlight the damaging and disease-causing effects of high doses of radiation. As there are limited facilities worldwide to perform the experiments, understanding of the cellular response to chronic radiation is not well known. To address this, I focused on characterising the response of primary cells isolated from neonatal foreskin donors and exposed to chronic radiation. Not surprisingly, results show that chronic radiation elicited many classic DNA-damage response outcomes such as …
abstract: It is well understood that radiation causes damage to DNA, which triggers a DNA-damage response often centred on the signalling pathways of ATM, with the subsequent involvement of proteins such as p53, p21 and H2AX. Many experiments have been performed with cell lines derived from different origins and donors which, while invaluable for studying specific effects, restrict direct assessment of response variability between different cells, tissues and individuals. This thesis investigates normal tissue responses to DNA damage from acute and chronic radiation, including exploration of cell-type and individual-specific differences in DNA-damage response. Due to the difficulty of obtaining different primary cell types of isogenic background (necessary to prevent confounding results by inter-individual variation), there are still unanswered questions regarding the extent and details of cell-type-specific responses to ionising radiation. I have developed a method for isolation of primary cells from human tissue and compared cellular outcomes and molecular signalling in response to an X-ray dose. Using these primary cells, I show that cell type causes far more variability in radiation response, with keratinocytes, which have highest p21 protein levels, being most susceptible to cell cycle arrest and senescence, while donor variability is limited. Another issue that has received insufficient attention is the biological effects of chronic radiation. Both experimental and epidemiological evidence highlight the damaging and disease-causing effects of high doses of radiation. As there are limited facilities worldwide to perform the experiments, understanding of the cellular response to chronic radiation is not well known. To address this, I focused on characterising the response of primary cells isolated from neonatal foreskin donors and exposed to chronic radiation. Not surprisingly, results show that chronic radiation elicited many classic DNA-damage response outcomes such as …
author: Lowe, Donna
language: eng
keywords: Cell type, DNA damage, Epigenetic, Histone, Inter-individual, Ionising radiation
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/73d114dd-6450-4c5b-b88d-d6b783845137/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2022-12-01
date modified: 2026-07-22T22:24:16Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.101536