William
Holley
Sponsor: Daniel Kliebenstein, Ph.D. Plant Sciences Specialized metabolites play critical roles in plant-environment interactions. We investigated how glucosinolate biosynthetic pathways evolve to create chemical diversity. The glucosinolates are a model class of specialized metabolites primarily found in the order Brassicales, and are diverse in the Brassicaceae family. To query how one enzyme evolves, we focused on variation in GSL- OH, that synthesizes 2-hydroxy-but-3-enyl glucosinolate. Phylogenetic analyses and complementation assays revealed extensive variation at the GSL-OH locus, including widespread independent gene losses, suggesting that gene loss contributes substantially to chemical diversification within the family. Moving to the Tropaeolaceae family, a chemical survey showed a novel tryptophane-derived glucosinolate, thought to have evolved later in Brassicales evolutionary history. This prompted us to examine the CYP79 enzyme family that catalyzes an early step in glucosinolate biosynthesis by directing tryptophan, phenylalanine, and methionine into the indolic, aromatic, and aliphatic pathways, respectively. Using functionally characterized Arabidopsis thaliana CYP79 protein sequences as bait in the blast-align-tree pipeline, homologs across Brassicales were identified and their functions predicted by phylogenetic similarity to A. thaliana. Ongoing complementation assays will test these predictions, enabling us to map the evolutionary origins of glucosinolate classes and assess the broader role of gene loss in shaping pathway diversification across the order. Characterizing PARP Inhibitor Induced Drug Tolerant Persistence in Advanced Cancer
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William Holley
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Targeting tumor cells with defects in homologous recombination using poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) has significantly improved the treatment of several cancers including that of the prostate. However, resistance development is common leading to progression and treatment failure. Preliminary data suggest that prolonged exposure to PARP inhibition induces prostate tumor cell adoption of a drug-tolerant persister (DTP) state that enables survival under therapeutic pressure and which promotes resistance. The emergence of DTP cells is a major obstacle to long-term treatment effectiveness, as these cells can serve as reservoirs for disease relapse. We hypothesize that the DTP state is a conserved cellular response across cancer types and that defining shared features of this state may reveal therapeutic opportunities. Building on prior research characterizing PARPi induced prostate cancer DTP cells, this project investigates breast, ovarian, and pancreatic cancer DTP cells. We identify phenotypic and molecular features associated with the DTP state using cell growth assays, colony formation assays, microscopy, and western blotting. By evaluating similarities and differences in DTP characteristics across cancer models, this work aims to assess the generalizability of the DTP state to support future efforts to target vulnerabilities specific to drug-tolerant tumor cells. Chemotherapy Agent Intercalation Mechanism Characterization via Electron Paramagnetic Resonance Spectroscopy Sydney Hollingsworth
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UC Davis / MED: Biochem & Molecular Med / 2026
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William Holley