Advisor(s)
Lalita Shevde
Committee Member(s)
Alexa Mattheyses
David Schneider
Elizabeth Worthey
John Parant
Rajeev Samant
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Pathology
Date of Award
1-6-2025
Abstract
Ribosome biogenesis, a complex and multi-step process that occurs predominantly in the nucleolus, plays a critical role in cellular function by mediating protein synthesis through the assembly of ribosomal RNAs (rRNAs) and ribosomal proteins into functional ribosomes. In cancer, dysregulation of this process is linked to the development of specialized ribosomes (onco-ribosomes) that support oncogenic translation programs, enhancing tumor progression and therapeutic resistance. This dissertation explores the interplay between ribosome biogenesis and cancer, focusing particularly on the role of RNA Polymerase I (RNA Pol I) activity under hypoxic conditions and rRNA modifications in breast cancer. My first study elucidates the upregulation of RNA Pol I activity in response to hypoxia, a common microenvironmental feature of solid tumors, particularly breast cancer. I demonstrate that stabilized hypoxia-inducible factor 1-alpha (HIF-1α) localizes to the nucleolus and directly interacts with rDNA promoters, augmenting rRNA synthesis. This interaction is critical for supporting the cellular adaptations required for invasion and metastasis. Inhibition of RNA Pol I shows potential to mitigate these hypoxia-induced processes. Further, I delve into the phenomenon of ribosome heterogeneity, which arises from epitranscriptomic modifications in rRNA and ribosomal protein compositions across different cell types and metabolic states. Through a systematic literature search, we identified 22 rRNA modifying proteins (RRMPs) that significantly contribute to rRNA modifications, impacting ribosome function. My analysis across various cancer types, with a focus on breast cancer, indicates that alterations in RRMPs' expression and mutation frequency are associated with aggressive cancer phenotypes and poor prognosis. TRMT112, a methyltransferase specifically modifying 18S rRNA at unique positions 1639 and 1832, emerges as a critical player in triple-negative breast cancer, suggesting its potential as a therapeutic target. Collectively, these findings highlight the critical role of ribosome biogenesis in cancer progression, underscoring the potential of targeting specific aspects of this process, such as RNA Pol I activity and rRNA modifications, as novel therapeutic strategies. This dissertation provides new insights into the molecular underpinnings of ribosome biogenesis in the oncogenic context, offering pathways for targeted interventions that could disrupt the translational control essential for cancer cell survival and proliferation.
ProQuest ID
Recommended Citation
Elhamamsy, Amr Rafat, "Elucidating The Impact Of Ribosome Biogenesis On Breast Cancer" (2025). All ETDs from UAB. 7302.
https://digitalcommons.library.uab.edu/etd-collection/7302
