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

• Main Author: Woo, Ren He
• Other Authors: Li Hoi Yeung
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2021
• Subjects: Science::Biological sciences::Molecular biology
• Online Access: https://hdl.handle.net/10356/152423
• Institution: Nanyang Technological University

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.