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DeRose, Victoria Sutton, Emily 2021-04-29T14:51:28Z 2021-04-29 https://hdl.handle.net/1794/26199 Platinum(II) chemotherapeutic agents represent a critical class of anticancer compounds. The clinical use of these compounds is limited by side effects and development of resistance. Despite these limitations, the three FDA approved Pt(II) drugs – cisplatin, carboplatin, and oxaliplatin – remain an important treatment option for many cancers. The molecular mechanisms of these drugs remain unresolved and are the subject of significant investigation. One area of investigation is the impact that Pt(II) compounds have on ribosome biogenesis and the nucleolus. Existing literature has shown that oxaliplatin, but not cisplatin or carboplatin, kill cancer cells via the ribosome biogenesis stress response. This work seeks to clarify the relationship between Pt(II) compounds and ribosome biogenesis stress, alternatively referred to as nucleolar stress. Chapter I provides background on Pt(II) chemotherapeutic agents, the nucleolus, and ribosome biogenesis. Chapter II uses a structure-activity approach to identify unique structural properties that are responsible for nucleolar stress induction as measured by the redistribution of the nucleolar protein nucleophosmin (NPM1) in A549 cells. Chapter III pairs NPM1 redistribution with pulse-chase radiolabeling assays and imaging of other nuclear and nucleolar proteins to establish that reduced transcription of ribosomal RNA transcripts is an early step responsible for nucleolar stress induction by oxaliplatin. Chapter IV summarizes existing methods that allow tracking of Pt(II) compounds in cells, and describes the development of an assay to identify binding sites of Pt(II) on DNA in cells. These analyses allow for a more comprehensive understanding of the relationship between Pt(II) compounds and nucleolar stress. 2022-03-17 en_US University of Oregon All Rights Reserved. Chemotherapeutics Molecular biology Nucleolar stress Nucleolus Platinum chemotherapeutics Ribosome biogenesis Platinum(II) Compounds and Nucleolar Stress Electronic Thesis or Dissertation Ph.D. doctoral Department of Biology University of Oregonopen.access