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Title: The role of TRF2 in regulating neural progenitor cells' proliferation and survival
Author: Muhammad Imran, Siti Aminah
ISNI:       0000 0004 9350 7168
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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The telomere repeat binding factor 2 (TRF2) plays an important role in protecting the telomere from any unwanted recombination and DNA fusion, which could cause DNA instability and cell death through t-loop formation and inhibition of the DNA Damage Response, such as the ATM. TRF2 protein has been previously identified as being highly expressed in the hESC-derived neural progenitor cells (NPCs). In the current study, we have reduced TRF2 expression in these NPCs by RNA knockdown and investigated the role of TRF2 in cell growth under various culture conditions. We have also overexpressed TRF2 in HEK293T cells to determine whether the effects of TRF2 are cell-specific or not. Under the routine culture condition (N2B27 + bFGF/EGF, 37°C, 5% CO2), high TRF2 expressing NPCs showed significantly higher growth and less apoptosis (p<0.01). However, under the various stress conditions (B27 withdrawal, oxidative stress and hypoxia), high TRF2 expressing cells seemed to exhibit more cell death than low TRF2 expressing cells within 1 hour of the treatment, indicating the involvement of TRF2 in the DNA damage response. Under the standard culture conditions, the expressions of ATM-dependant DDR factors were significantly lower in the high TRF2 expressing NPCs. However, the comet assay analysis showed that the high TRF2 expressing cells has a higher DNA Double Strand Breaks (DDSB), which is contradictory to the protein expressions of the DNA damage markers. The difference in proliferation and apoptosis were also observed in the TRF2 over-expressing 293T cells as compared to the control, which shows the function of TRF2 is not cell specific. Our results indicate that TRF2 might also be involved in cellular survival and/or cell death in addition to its regulation on telomeres. Under standard culture conditions, the higher TRF2 expression seems to help in terms of proliferation or protecting the cells against apoptosis, which suggest that TRF2 may have a protective function in cells. However, in the stress conditions, TRF2 seems to have an adverse effect on the cells, which could be due to the involvement of TRF2 with the DNA damage response pathway. These results might contribute to further understand the function of TRF2 in the DDR and in cell survival.
Supervisor: Cui, Wei Sponsor: Mara, Malaysia
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral