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PUS7-tRNA axis in translational control of MYC-driven transcription and metabolic reprogramming

Award Number: R01CA190429
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2014
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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View Award Description

PUS7-tRNA axis in translational control of MYC-driven transcription and metabolic reprogramming - MYC oncoproteins (MYC/MYCN/MYCL) drive transcriptional programs that fuel proliferation, metabolic reprogramming, and tumorigenesis, yet how translation is rewired to execute these programs remains unclear. We propose that oncogene-directed tRNA pseudouridylation rewires translation to implement and reinforce oncogenic programs. Our preliminary data show that MYC upregulates the pseudouridine synthase PUS7 and that PUS7-dependent tRNA pseudouridylation maintains tRNAGln and tRNAVal pools, enabling efficient translation of (i) glutamine-rich transcription factors and coactivators that reinforce MYC transcription and (ii) valine-rich, nuclear-encoded electron transport chain (ETC) subunits that preserve redox required for de novo pyrimidine synthesis. We hypothesize that MYC-induced, PUS7-dependent tRNA pseudouridylation biases translation by amino-acid content, thereby enabling MYC transcriptional and metabolic programs. Aim 1 will define the MYC–PUS7–tRNA axis. Our hypothesis is that MYC/MYCN induction increases PUS7-dependent Ψ13 on tRNAGln and tRNAVal, specifically elevating their abundance. We will map tRNA Ψ by BID-seq and nanopore-seq after MYC/MYCN activation, quantify tRNAGln and tRNAVal abundance and aminoacylation by tRNA-seq/RT-PCR and charging assays. These studies will map a mechanistic path from MYC to tRNA pseudouridylation, abundance, and charging. Aim 2 will test how the PUS7–tRNAGln axis reinforces MYC transcription. With MYC/MYCN induction and PUS7 or tRNAGln knockdown or overexpression, we will quantify translation of glutamine-rich transcription factors and coactivators (Ribo-seq, nascent-protein assays, targeted proteomics) and measure MYC transcriptional output (RNA-seq, ChIP-seq, ATAC-seq). Dietary glutamine restriction will be used as a surrogate for tRNAGln loss to evaluate this axis in xenografts. These studies will demonstrate causally that the PUS7–tRNAGln axis elevates translation of glutamine-rich transcriptional coactivators to sustain MYC-driven transcription in cells and tumors. Aim 3 will test how the PUS7–tRNAVal axis enables MYC-driven de novo pyrimidine synthesis. With MYC/MYCN induction and PUS7 or tRNAVal knockdown or overexpression, we will assess translation of valinerich ETC subunits (Ribo-seq, targeted proteomics, nascent-protein assays) and define redox coupling to pyrimidine synthesis (stable-isotope tracing, mitochondrial assays). Dietary valine restriction will be used as a surrogate for tRNAVal loss to test this pathway in vivo. These studies will establish a causal linkage from MYC via PUS7–tRNAVal to ETC protein production and de novo pyrimidine synthesis. Animal studies in Aims 2 and 3 are essential to test whether the proposed translational mechanisms affect MYC-driven tumor growth and associated transcriptional and metabolic pathways in vivo. These studies require intact tumor–host nutrient exchange, systemic nutrient availability, and physiologic tumor growth responses that cannot be fully recapitulated in cell culture or other in vitro systems. Impact. Completion of the project will establish tRNA pseudouridylation as a dynamic, epigenetic mechanism of translational reprogramming that executes and reinforces MYC programs, revealing actionable dependencies (PUS7, specific tRNA pools, amino-acid-content-biased translation) for therapeutic targeting in MYC-driven cancers.


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 = $372,500 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	000	12	7/10/2026	COMPETING CONTINUATION	$372,500
														Subtotal = $372,500

Issue Date FY: 2024 ( Subtotal = $335,053 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	000	11	6/17/2024	NON-COMPETING CONTINUATION	$335,053
														Subtotal = $335,053

Issue Date FY: 2023 ( Subtotal = $345,634 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	000	10	6/21/2023	NON-COMPETING CONTINUATION	$345,634
														Subtotal = $345,634

Issue Date FY: 2022 ( Subtotal = $333,283 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	005	9	5/13/2022	NON-COMPETING CONTINUATION	$333,283
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	004	8	1/19/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$94,829
2022	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	7	11/15/2021	NON-COMPETING CONTINUATION	-$333,476
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	001	8	11/15/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$333,476
2022	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	003	7	1/19/2022	NON-COMPETING CONTINUATION	-$32,274
2022	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	002	6	1/19/2022	COMPETING CONTINUATION	-$62,555
														Subtotal = $333,283

Issue Date FY: 2021 ( Subtotal = $365,750 )
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	002	7	6/23/2021	NON-COMPETING CONTINUATION	$365,750
2021	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	001	6	3/30/2021	COMPETING CONTINUATION	$17,013
2021	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	5	3/30/2021	NON-COMPETING CONTINUATION	-$17,013
														Subtotal = $365,750

Issue Date FY: 2020 ( Subtotal = $365,750 )
2020	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	001	6	7/1/2020	COMPETING CONTINUATION	$365,750
2020	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	5	7/1/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $365,750

Issue Date FY: 2018 ( Subtotal = $315,400 )
2018	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	5	7/24/2018	NON-COMPETING CONTINUATION	$315,400
														Subtotal = $315,400

Issue Date FY: 2017 ( Subtotal = $315,400 )
2017	2017	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	4	7/31/2017	NON-COMPETING CONTINUATION	$315,400
														Subtotal = $315,400

Issue Date FY: 2016 ( Subtotal = $315,400 )
2016	2016	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	3	7/29/2016	NON-COMPETING CONTINUATION	$315,400
														Subtotal = $315,400

Issue Date FY: 2015 ( Subtotal = $315,400 )
2015	2015	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	2	7/23/2015	NON-COMPETING CONTINUATION	$315,400
														Subtotal = $315,400

Issue Date FY: 2014 ( Subtotal = $313,671 )
2014	2014	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	1	9/15/2014	NEW	$313,671
														Subtotal = $313,671

Grand Total All Awards = $3,693,241

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PUS7-tRNA axis in translational control of MYC-driven transcription and metabolic reprogramming

Award Number: R01CA190429

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2014

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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