Vizeacoumar, FrancoFreywald, Andrew2024-07-1220242024-062024-07-12June 2024https://hdl.handle.net/10388/15803Over the past two decades, synthetic lethality (SL) has emerged as a promising strategy to selectively target cancer cells. Synthetic lethal interaction (SLI) occurs when the simultaneous inactivation of two genes results in cell death, while the inactivation of each gene individually has no effect on cell survival. This strategy is particularly advantageous when one of the genes involved is cancer-specific, providing a unique "tumor-specific context" or biomarker, and the other gene becomes a "vulnerable target" for eliminating cancer cells. Recent therapeutic successes employing synthetic lethality strategies have focused on genes associated with DNA damage response (DDR) pathways, suggesting that targeting these pathways could efficiently eliminate cancer cells. This project aims to identify SLIs involving DDR genes, with a specific focus on CDKN1A, a gene commonly lost in cancers. Using the concept of gene essentiality, we employed a predictive approach to identify SLIs for 161 DDR genes, focusing specifically on those downregulated in cancers. To validate our predictions, we conducted experimental analyses of SLIs between CDKN1A and members of the BAF complex using CRISPR/Cas9 gene knockouts followed by clonogenic assays. Analysis of the clonogenic assay outcomes revealed a significant trend among certain members of the BAF complex, with most of these genes associated with the PBAF complex, highlighting the potential significance of PBAF complex components in synthetic lethal interactions with CDKN1A-deficient cells. Identification of synthetic lethal interactions between CDKN1A and specific members of the BAF complex, particularly those associated with the PBAF complex, suggests promising avenues for further exploration in cancer therapy. These findings contribute to both functional understanding and the identification of therapeutically relevant targets for treating cancers characterized by CDKN1A deficiency.application/pdfenSynthetic lethalityDNA damageCDKN1AThesis2024-07-12