Contribution of metabolic alterations to genome instability and its association with cancer development

Metabolic reprogramming could promote genome instability, causing normal cells to acquire somatic mutations that favours tumourigenesis. To investigate this, ATP citrate lyase (ACLY) was overexpressed in normal epithelial cells, where it induced the formation of micronuclei, nuclear budding and nucl...

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Main Author: Woo, Ren He
Other Authors: Li Hoi Yeung
Format: Thesis-Doctor of Philosophy
Language:English
Published: Nanyang Technological University 2021
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Online Access:https://hdl.handle.net/10356/152423
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-1524232023-02-28T18:50:29Z Contribution of metabolic alterations to genome instability and its association with cancer development Woo, Ren He Li Hoi Yeung School of Biological Sciences HYLi@ntu.edu.sg Science::Biological sciences::Molecular biology Metabolic reprogramming could promote genome instability, causing normal cells to acquire somatic mutations that favours tumourigenesis. To investigate this, ATP citrate lyase (ACLY) was overexpressed in normal epithelial cells, where it induced the formation of micronuclei, nuclear budding and nucleoplasmic bridges in cells. These nuclear abnormalities were found to be caused by DNA double stranded breaks (DSBs). It was discovered that phosphorylated ATR and total Chk1 were deregulated through the proteosomal degradation pathway, which could have caused cells to become susceptible to DSBs via replication stress. Furthermore, p53 phosphorylation was found to be decreased in the presence of oxidative stress. This could have enabled cells to sustain cell growth without undergoing apoptosis, causing DSBs to be unrepaired or misrepaired. These events could account for the formation of nuclear abnormalities. These cells were also found to exhibit increased anchorage-independent proliferative fitness. Hence, metabolic alterations induced by ACLY contributes to genome instability. Doctor of Philosophy 2021-08-13T02:40:10Z 2021-08-13T02:40:10Z 2021 Thesis-Doctor of Philosophy Woo, R. H. (2021). Contribution of metabolic alterations to genome instability and its association with cancer development. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/152423 https://hdl.handle.net/10356/152423 10.32657/10356/152423 en This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). application/pdf Nanyang Technological University
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Biological sciences::Molecular biology
spellingShingle Science::Biological sciences::Molecular biology
Woo, Ren He
Contribution of metabolic alterations to genome instability and its association with cancer development
description Metabolic reprogramming could promote genome instability, causing normal cells to acquire somatic mutations that favours tumourigenesis. To investigate this, ATP citrate lyase (ACLY) was overexpressed in normal epithelial cells, where it induced the formation of micronuclei, nuclear budding and nucleoplasmic bridges in cells. These nuclear abnormalities were found to be caused by DNA double stranded breaks (DSBs). It was discovered that phosphorylated ATR and total Chk1 were deregulated through the proteosomal degradation pathway, which could have caused cells to become susceptible to DSBs via replication stress. Furthermore, p53 phosphorylation was found to be decreased in the presence of oxidative stress. This could have enabled cells to sustain cell growth without undergoing apoptosis, causing DSBs to be unrepaired or misrepaired. These events could account for the formation of nuclear abnormalities. These cells were also found to exhibit increased anchorage-independent proliferative fitness. Hence, metabolic alterations induced by ACLY contributes to genome instability.
author2 Li Hoi Yeung
author_facet Li Hoi Yeung
Woo, Ren He
format Thesis-Doctor of Philosophy
author Woo, Ren He
author_sort Woo, Ren He
title Contribution of metabolic alterations to genome instability and its association with cancer development
title_short Contribution of metabolic alterations to genome instability and its association with cancer development
title_full Contribution of metabolic alterations to genome instability and its association with cancer development
title_fullStr Contribution of metabolic alterations to genome instability and its association with cancer development
title_full_unstemmed Contribution of metabolic alterations to genome instability and its association with cancer development
title_sort contribution of metabolic alterations to genome instability and its association with cancer development
publisher Nanyang Technological University
publishDate 2021
url https://hdl.handle.net/10356/152423
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