Zou, LeeMorris, JamesOppong-Holmes, Awura Ama2023-01-2420232023-01-232023Oppong-Holmes, Awura Ama. 2022. The Role of RAD51AP1 in Drug Resistance in Glioblastoma Cells. Master's thesis, Harvard University Division of Continuing Education.30247961https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37374088The use of PARP inhibitors is becoming more prevalent in various cancer therapies however due to drug resistance, genetics, and cancer metastasis, the impetus to finding novel effective therapeutics still exists. Exploring RAD51AP1’s role in PARP inhibitor resistance gives insight to whether the protein is a viable target for cancer therapy through the investigation of the change in drug sensitivity in the presence and absence of the protein. One of the most prevalent mechanisms in drug resistance is the restoration of defective homologous recombination repair (HR) pathway during PARP inhibition (PARPi) treatment. This is due to the deactivation of the synthetic lethality pathway by which PARPi treatments predominantly work. RAD51 recombinase plays a major role of facilitating HR repair with the help of RAD51AP1, in the DR-loop formation required for the process (Ouyang et al., 2021). In addition, there is evidence of the knockout of RAD51AP1 leading to stunted growth of intrahepatic cholangiocarcinoma cells and the reduction in expression leading to decreased cell proliferation in cancer cells (Obama et al., 2008). Exploring the role of RAD51AP1 will help assess whether this protein is a viable target in restoring synthetic lethality for the resumption of PARPi therapeutic effects or if there are other pathways by which it operates to produce similar therapeutic effects to the observed stunted growth. The experimental results in the glioblastoma cell lines proved to be quite promising with decreased HR efficiency, and increased TMZ drug sensitivity observed in pooled RAD51AP1 knockout cells and single cell clones. These pooled knockout cells also showed increased sensitivity to PARPi, however, not in the single cell clone pools.application/pdfenGlioblastomahomologous recombinationHRPARPPARPiRAD51AP1BiologyThesis or Dissertation2023-01-24awuraamaoppongholmes