Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Molecular mechanisms of transuridyltransferase activity and substrate specificity

Award Number: F32GM163387
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2027
PERIOD OF PERFORMANCE END DATE: 01/31/2028

Group Awards By:

View Award Description

Molecular mechanisms of transuridyltransferase activity and substrate specificity - SUMMARY Cells use 3’ tagging of RNA to control their fate. For example, uridine tails can mark RNA for further processing or degradation. Proper biogenesis of let-7, a microRNA that regulates cellular proliferation, often requires 3’ monouridylation of its precursor pre-let-7. In contrast, oligouridylation of pre-let-7 leads to its degradation, allowing the expression of let-7’s oncogene targets. Both mono- and oligouridylation of pre-let-7 are carried out by the same enzymes, the redundant terminal transuridyltransferases (TUTases) TUT4 and TUT7 (TUT4/7). Pre-let-7 oligouridylation requires the cofactor Lin28a, which is expressed in stem-like cell states and certain cancers. TUT4/7 oligouridylate additional substrate RNAs of distinct structure and sequence from pre- let-7s, such as mRNAs with short polyadenylated (poly(A)) tails. Curiously, this occurs even in the absence of Lin28. Despite TUT4/7’s established importance for cell identity, the extent of their potential substrates, and how they select these substrates, remains a key question. The goal of this proposal is to decipher the mechanism of TUT4/7 activity on different substrates through the following aims: (1) Examine the mechanism of TUT4/7 uridylation of poly(A) substrates, and (2) Identify additional TUT4/7 substrates. Crystallography data for the catalytic domain suggest similarities in the basic uridylation mechanism for oligouridylated and poly(A) substrates. This highlights a gap in our understanding: what are the molecular determinants of binding to RNAs with structural differences and requirements for activity (e.g., poly(A) oligouridylation does not require Lin28a)? Aim 1 will focus on stabilizing near-full-length TUT4/7 in complex with poly(A) substrate for cryo-EM studies. Preliminary data indicate that limiting a disordered region that could contribute to protein instability results in an active enzyme that can be used for structural studies. Alternative approaches include modifications to sample conditions and a synthetic substrate with a chemical trap. Aim 2 will investigate the extent of TUT4/7 substrates. I will use a click chemistry strategy to label, capture, and sequence oligouridylated cellular RNAs. Combined, these studies will reveal important cellular RNA regulation mechanisms relevant to the control of cellular differentiation and cancer progression. For success in this project, I will draw on my existing expertise in protein biochemistry and chemical biology, and build my structural biology skillset. I will train under Dr. Leemor Joshua-Tor, an expert in structural characterization of nucleic acid/protein complexes, with the support of first-rate core facilities and educational resources at Cold Spring Harbor Laboratory. This work will provide a strong foundation for my career in research.


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 = $76,780 )
2026	2026	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPG HBR	NY	11724	SUFFOLK	USA	Biomedical Research and Research Training	000	1	7/28/2026	NEW	$76,780
														Subtotal = $76,780

Grand Total All Awards = $76,780

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Molecular mechanisms of transuridyltransferase activity and substrate specificity

Award Number: F32GM163387

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2027

PERIOD OF PERFORMANCE END DATE: 01/31/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer