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Translation of small open reading frames in 3'UTR enhances translation of canonical open reading frames

Award Number: K00CA253719
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Translation of small open reading frames in 3'UTR enhances translation of canonical open reading frames - Project Summary Ribosome and proteomic profiling have revealed a large number of small translated open reading frames (ORF) within previously described “untranslated regions” (UTRs) and long non-coding RNAs. While some of the small ORFs depend on the encoded peptide to function in various fundamental processes (e.g., development). Translation of small ORFs in the 5’UTR, known as upstream-ORFs (uORFs), usually represses gene expression, independent of the encoded peptide. Small ORFs have also been reported in 3'UTR, termed downstream ORF (dORF). However, the dORF function and their relationship to human health and disease remain unknown. I characterized dORFs from human and zebrafish using ribosome profiling data. My preliminary data indicates, contrary to uORFs, translation of dORFs (small ORF in the 3’UTR) strongly enhances translation of the canonical ORFs and remains an uncharacterized regulatory mechanism across vertebrates. The objectives are: 1) Dissect at the single molecular level how dORF enhances translation of the canonical CDS. And 2) Determine whether alternative polyadenylation in cancer influences dORF regulation to cause cancer. The rationale for the proposed research is to gain a mechanistic understanding of dORF-mediated regulation and to assess the possible biological importance of dORF dysregulation under disease conditions (e.g. Cancer). This proposal is conceptually innovative as it is based on the exploration of a novel, yet widespread translation regulatory mechanism conserved across vertebrates. Technically, this proposal will combine single molecular imaging, genomic profiles (RNA-seq, Ribosome profiling), and reporter approaches in different human cell lines (including cancer cells) and published patient data. The outcomes from this project will emphasize the role of ribosome as a master gene expression regulator, and shield light on the importance of small ORFs. This translation kinetics work about dORF will provide critical insights into the molecular mechanism of this uncharacterized regulatory pathway. Exploring dORF dysregulation in cancer due to APA will highlight the mRNA itself as disease driver even without any mutation in DNA, and it also indicates possible clinical impact of dORF to detect and even cure cancer. My long-term interest is to study gene expression dysregulation in cancer. This training award will increase my knowledge background of cancer biology, molecular biology and bioinformatics. It will also promote the technical training of single molecular imaging, ribosome profiling, cell biology assays for cancer. Overall, this proposal will help me for future independent cancer molecular/genomic career.


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: 2025 ( Subtotal = $117,062 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	6	7/23/2025	NON-COMPETING CONTINUATION	$117,062
														Subtotal = $117,062

Issue Date FY: 2024 ( Subtotal = $111,783 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	5	7/18/2024	NON-COMPETING CONTINUATION	$111,783
														Subtotal = $111,783

Issue Date FY: 2023 ( Subtotal = $98,334 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	001	4	7/25/2023	NON-COMPETING CONTINUATION	$98,334
2023	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	3	4/18/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $98,334

Issue Date FY: 2022 ( Subtotal = $94,997 )
2022	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	3	8/18/2022	EXTENSION WITH OR WITHOUT FUNDS	$94,997
														Subtotal = $94,997

Grand Total All Awards = $422,176

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Translation of small open reading frames in 3'UTR enhances translation of canonical open reading frames

Award Number: K00CA253719

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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