Description
- Abstract:
- Base excision repair (BER) is a critical DNA repair pathway that resolves base and single-strand DNA damage to help maintain genomic stability. Key BER proteins [e.g., XRCC1, DNA polymerase β (POLB), DNA ligase III (LIG3), and aprataxin (APTX)] operate in a coordinated manner, along with poly(ADP-ribose) polymerases 1 and 2, to facilitate efficient repair. In multiple studies, disruption of poly(ADP-ribose) (PAR) metabolism, by inhibiting poly(ADP-ribose) glycohydrolase (PARG), has been demonstrated to impair DNA repair and induce replication stress. However, the contribution of individual BER components to the cellular response to PARG inhibition remains poorly defined in the literature. In this study, we have evaluated the roles of selected BER factors in modulating cellular sensitivity to PARG inhibition in ovarian cancer cells. More specifically, ES-2 cells were subjected to siRNA-mediated knockdown of XRCC1, POLB, LIG3, and APTX, and protein depletion was confirmed by immunoblotting. Cell viability was evaluated following treatment with the PARG inhibitor PDD00017272. Depletion of XRCC1 was correlated with a consistent increase in sensitivity to PARG inhibition across biological replicates. LIG3 knockdown also reduced cell viability in response to PARG inhibition, though the magnitude of this effect varied. In contrast, POLB depletion produced modest, less consistent changes, whereas APTX knockdown had minimal impact on the cellular response under the conditions tested. Overall, these results suggest that BER proteins play distinct roles in how cells respond to PARG inhibition. XRCC1, in particular, stands out as a key factor in maintaining cell viability under these conditions. While these findings are compelling, the variability within certain experimental groups and our limited number of biological replicates suggests that these results should be viewed as preliminary. Therefore, in future studies, it will be essential to use a broader range of experimental models to pin down the exact mechanisms at play.
- Notes:
- Thesis (Sc. M.)--Brown University, 2026
Citation
He, Zhiying,
"Differential Effects of Base Excision Repair Factor Depletion on Cellular Sensitivity to PARG Inhibition in Ovarian Cancer Cells"
(2026).
Biology and Medicine Theses and Dissertations, Biotechnology.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:e5bdpa2d/
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Biology and Medicine Theses and Dissertations
Theses and Dissertations for the Biology and Medicine department....