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High-Throughput Measurements of RNA-Mediated Regulation of Gene Expression and Oncogenesis

Award Number: F30CA287739
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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High-Throughput Measurements of RNA-Mediated Regulation of Gene Expression and Oncogenesis - Project Summary Dysregulation of RNA-binding protein (RBP)-RNA interactions impacts the coordination of RNA fate with severe implications for human health. RBPs interact directly with RNA processing machinery to modulate RNA localization, degradation, and translation independently of transcriptional regulation. Disruptions in RBPs or their RNA binding sites can lead to fluctuations in oncogene or tumor-suppressor gene expression and malignant changes in cellular homeostasis. Understanding the molecular functions of RBPs in regulating gene expression is then imperative for predicting metastatic progression in cancers with RBP mutant gene signatures. Recent work has led to the discovery of thousands of human RBPs, but much less has been done to systematically describe the function that each protein and its individual domains have on regulating their RNA partners. Additionally, the functional organization of RBPs beyond their distinct and generally well-characterized RNA-binding domains (RBDs) is not fully understood. Until recently, it was assumed that RBPs were effectively non-modular outside of RBDs; however, current studies suggest that RBPs may be composed of separable ‘effector’ domains that interact with processing machinery and promote regulatory activity. I hypothesize that most RBPs contain distinct effector domains that post-transcriptionally regulate protein abundance through interactions with cellular machinery that controls RNA decay or translation. The Bintu lab has developed a high-throughput recruitment assay to recruit 80 amino acid protein portions, or tiles, to a synthetic DNA reporter gene. I propose to extend this methodology to identify functional effector domains within human RBPs, where they also may be more sensitive to oncogenic mutation. First, I will use a high-throughput assay I recently developed to recruit tens of thousands of protein tiles to a synthetic reporter RNA, evaluate their effects on downstream protein expression, and determine the mechanism by which they regulate RNA levels. This will allow me to identify annotated oncogenic mutations that overlap effector domains and likely cause disease by disrupting RBP regulatory activity. Second, it is currently difficult to predict how loss of RBP activity affects a single bound transcript, largely because RBPs bind at different positions and in different copy numbers on each of their multiple partner RNAs. I will quantitatively compare how variation in RBP and effector domain positioning and occupancy along transcripts affects gene expression and eventual different cancer phenotypes. Finally, I will conduct a mechanistic investigation into METTL3, a known RNA-modifying enzyme whose overexpression is believed to drive the development of multiple cancers. I will determine its RNA regulatory potential independent of modification writing and query the direct correlation between RNA modifications and overall expression. This work will be the first to systematically identify functional domains in RBPs and will increase understanding of how dysregulation of RBP function leads to cancer through altered interactions with crucial cellular machinery.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $42,224 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	3	3/24/2026	NON-COMPETING CONTINUATION	$42,224
														Subtotal = $42,224

Issue Date FY: 2025 ( Subtotal = $42,224 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	2	5/29/2025	NON-COMPETING CONTINUATION	$564
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	2	2/19/2025	NON-COMPETING CONTINUATION	$41,660
														Subtotal = $42,224

Issue Date FY: 2024 ( Subtotal = $51,237 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	1	3/4/2024	NEW	$0
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	002	1	5/7/2024	NEW	$1,280
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	1	3/4/2024	NEW	$49,957
														Subtotal = $51,237

Grand Total All Awards = $135,685

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High-Throughput Measurements of RNA-Mediated Regulation of Gene Expression and Oncogenesis

Award Number: F30CA287739

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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