Sharif, Ahmad Anwar Dawood;
(2024)
The regulation of cell cycle progression, DNA damage response and repair by NDR1/2 protein kinases.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
The nuclear Dbf2-related (NDR) family of protein kinases has received significant attention in recent years due to their important roles in regulating embryonic development, centrosome duplication, and apoptosis. In this regard, recent studies have proposed NDR1/2 as potential players in the DNA damage response (DDR). In this research project, we hypothesised that NDR1/2 may be involved in DDR and cell cycle progression by regulating MOB2, a novel DDR protein involved in DDR, cell cycle progression, and homologous recombination repair (HR). Significantly, we found that under normal growth conditions, NDR1/2 are necessary to prevent the accumulation of endogenous unrepaired DNA damage in untransformed cell lines. NDR1/2 further support DDR and cell cycle checkpoint activation. The biological significance of NDR1/2 appears to be linked with MOB2 since normal protein levels of NDR1/2 are required to maintain the protein stability of MOB2 in human cell lines and murine tissue samples. Equally important, the kinase activities of NDR1/2 are not required to maintain normal protein levels of MOB2 and are dispensable for normal cell proliferation. We also revealed that NDR1/2-deficient cell lines display impaired HR as judged by RAD51 foci formation. Intriguingly, we further reported that defective HR due to NDR1/2 co-depletion may provide a novel translational approach for future clinical studies. Notably, NDR1/2 co-knockdown renders human cancer cell lines vulnerable to ionising radiation (IR), chemotherapeutic agents, and poly(ADP-ribose) polymerase (PARP) inhibitors. Collectively, these findings cumulatively suggest that NDR1/2 could be considered as a potential novel DDR candidates for targeted therapies in cancers with deficiencies in HR.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The regulation of cell cycle progression, DNA damage response and repair by NDR1/2 protein kinases |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10195188 |
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