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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| Format: | Thesis-Doctor of Philosophy |
| Language: | English |
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Nanyang Technological University
2021
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| Online Access: | https://hdl.handle.net/10356/152423 |
| _version_ | 1824455695319171072 |
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| author | Woo, Ren He |
| author2 | Li Hoi Yeung |
| author_facet | Li Hoi Yeung Woo, Ren He |
| author_sort | Woo, Ren He |
| collection | NTU |
| 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. |
| first_indexed | 2025-02-19T03:42:18Z |
| format | Thesis-Doctor of Philosophy |
| id | ntu-10356/152423 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:42:18Z |
| publishDate | 2021 |
| publisher | Nanyang Technological University |
| record_format | dspace |
| spelling | ntu-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 |
| spellingShingle | Science::Biological sciences::Molecular biology Woo, Ren He Contribution of metabolic alterations to genome instability and its association with cancer development |
| title | 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_short | 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 |
| topic | Science::Biological sciences::Molecular biology |
| url | https://hdl.handle.net/10356/152423 |
| work_keys_str_mv | AT woorenhe contributionofmetabolicalterationstogenomeinstabilityanditsassociationwithcancerdevelopment |