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Investigating the regulation of DNA non-homologous end-joining through Ku70/80 interacting factors 10.17863/CAM.37852 Sivapalan, Rohan Pakiaraj Jackson, Stephen DNA double-strand breaks are the most deleterious type of DNA damage that cells experience, which makes the study of double-strand break repair extremely important. Unrepaired or aberrantly repaired DNA can result in changes to core genes with critical function and thus lead to multiple diseases. Two main repair pathways for double-strand breaks exist: homologous recombination (HR) and non-homologous end-joining (NHEJ). Whilst the regulation of HR has been heavily investigated, the regulation of NHEJ remains to be fully explored. The aim of this thesis is to investigate the regulation of DNA NHEJ through interacting factors of the core NHEJ protein heterodimer, Ku70/80 (Ku). This thesis consists of three main research projects. The first, explores the potential role of the CUL4 substrate adaptor, WDR76, in the removal of Ku from sites of DNA damage. Data presented here highlight a role of WDR76 in the DNA damage response (DDR), and through effects on Ku removal kinetics, suggest a role for WDR76 in the regulating NHEJ. The second research project investigates a potential cyclin-dependent kinase phosphorylation site on the protein paralog of XRCC4 and XLF (PAXX). As PAXX is a Ku interactor with a role in NHEJ, the effect of PAXX phosphorylation is investigated as a potential NHEJ regulatory system. Lastly, I investigate the role of the RecQ helicase WRN, whose precise roles in the DDR are unclear. As an interactor of both HR and NHEJ proteins, WRN may affect the regulation of both pathways. WRN knockout cells were generated and a CRISPR-Cas9 screen performed to identify suppressors of WRN sensitivity to DNA damage. The targets identified offer insights into WRN function. University of Cambridge 2019-07-20 Thesis Doctoral Doctor of Philosophy (PhD) en BBSRC Horizon Discovery Steve Jackson Laboratory https://www.repository.cam.ac.uk/handle/1810/290644 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/92aa78d7-e51c-426c-904a-591f13ad394b/download 6dea9d54192b8d3db93cb9787387aac5 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/44f0776b-e123-48ef-a0a1-c350efa7130a/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ DNA repair DNA damage Molecular Biology Cancer biology NHEJ HR Ku