PROJECT 3 – BIOLOGY OF DNA DEAMINASES IN CANCER

PROJECT 3 – BIOLOGY OF DNA DEAMINASES IN CANCER ABSTRACT APOBEC3 (A3) enzymes are a major cause of genomic mutation in many different cancers. A3s are single- stranded (ss)DNA cytosine to uracil (C-to-U) deaminases that function normally in innate antiviral immunity, but they often become expressed aberrantly in cancer and promote DNA damage, mutagenesis, and genome instability. Work in the original funding period has converged on APOBEC3A (A3A) and APOBEC3B (A3B) as the main etiologic agents. However, major gaps remain in understanding how these two enzymes become dysregulated in tumor cells and contribute to driving tumor progression and poor clinical outcomes. To address these gaps and to test our Program’s overarching hypothesis that disabling A3A/B activity will slow tumor evolution, we are pursuing two comprehensive specific aims. Aim 1 studies are focused on investigating A3A/B regulation at the protein level (upstream of ssDNA deamination). Several complementary approaches including genetics, proteomics, and informatics will be used to understand the molecular mechanisms of A3A/B regulation in normal and tumor cells. Aim 2 studies are focused on investigating the proteins and pathways that compete for uracil lesion processing and ultimately elaborate the different mutational outcomes that are observed (downstream of ssDNA deamination). Aim 2 studies will leverage human cellular systems as well as novel murine models for A3A/B mutagenesis, where these enzymes are individually capable of driving tumor formation. Importantly, Aim 2 studies will also utilize cellular and in vivo systems to assess candidate A3A/B inhibitors from the combined efforts of this Program and ultimately test our central hypothesis that tumor evolution can be slowed to prevent detrimental outcomes.