Project Summary/Abstract The ultimate goal of this mPI proposal is to address a fundamental gap in knowledge on the role of acetyl-CoA metabolic reprogramming in regulating cyclin E-high ovarian cancer DNA damage response, transformation, and response to therapy. The results from these studies could have a significant impact on the treatment of the ~20% of high grade serous ovarian cancer (HGSOC) patients with high cyclin E expression, which are resistant to emerging PARP inhibitor therapies due to proficiency in homologous recombination (HR)-mediated DNA repair. This research plan focuses on assessing the experimentally and mechanistically determining the spaciotemporal metabolic reprogramming of acetyl-CoA on histone hyperacetylation and enhancement of HR-mediated DNA repair and whether this pathway can be targeted in cyclin E-high HGSOC patients in combination with emerging PARP inhibitor therapies to obtain a synthetic lethality and sustained therapeutic response. The proposed studies are based on our preliminary findings that glucose-derived acetyl-CoA is upregulated in cyclin E-high cells, acetyl-CoA is spatially regulated in the cytoplasm and nucleus, and cyclin E-high cells display hyperacetylation of histones known to be involved in HR repair. In line with these data, we will explore two overarching scientific aims: 1) quantitatively dissect acetyl-CoA metabolic reprogramming in cyclin E-high HGSOC and its contribution to HR-mediated DNA repair; and 2) to determine whether acetyl-CoA mediated epigenetic changes contributes to ovarian tumorigenesis and therapeutic response. The completion of the scientific aims of this proposal will not only provide new mechanistic insights into the interplay between the acetyl-CoA-mediated metabolic-epigenetic axis during ovarian tumorigenesis, but will also establish targeting this axis as a strategy to improve therapeutic outcome for HGSOC patients with high cyclin E. The proposed research is of high impact because the mechanistic underpinning of these pathways has the potential to transform the management of HGSOC patients with high cyclin E. As PARP inhibitors are being developed for many cancer types, studies will have far-reaching implications for identifying novel strategies to inhibit HR-mediated DNA repair and develop future cancer therapeutics strategies for a wide range of patients.