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Role of Protein N-Myristoylation in Driving DNA Damage Response

Award Number: R00GM157498
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Role of Protein N-Myristoylation in Driving DNA Damage Response - DNA damage response (DOR) is crucial for maintaining genome stability, with its dysregulation implicated in various diseases. Post-translational modifications (PTMs) orchestrate DOR, influencing vital signaling pathways for genomic stability. Myristoylation, catalyzed by N-myristoyl transferase (NMT) 1 and 2, has emerged as a pivotal PTM that involves a range of biological processes. Despite its potential significance, a knowledge gap persists regarding the role of myristoylation in DOR. My preliminary data reveal a link between reduced myristoylation expression and heightened genomic instability. Utilizing quantitative proteomics, 14 myristoylated candidates within key DOR proteins were identified, with four overlapping the interactome of NMT1 and NMT2. Validation studies confirmed myristoylation on XRCC6 (Ku70), a key protein in the non-homologous end-joining pathway of double-strand break repair. These findings form the basis for the hypothesis that myristoylation actively propels DOR pathways by influencing the dynamics and functions of key proteins pivotal to DOR regulation. This project systematically investigates the role of myristoylation in DOR. Aim 1 delves into the association of myristoylation, modulated by NMT1 and NMT2, with genomic stability and DOR. This includes assessing the impact of myristoylation on DNA repair mechanisms and dissecting the interactome of NMT1 and NMT2 in response to various DNA damage agents. Aim 2 focuses on the detailed characterization of myristoylation on KU70, including the identification of specific myristoylation sites, evaluation of their impact on protein localization and stability, elucidation of functional consequences in DNA repair, and investigation of regulatory mechanisms. Transitioning into the ROO phase in Aim 3, I will build upon the insights gained during the K99 phase, leveraging them to validate and characterize additional myristoylated DOR candidates identified through proteomic screening. This phase aims to develop therapeutic implications based on a comprehensive understanding of myristoylation's regulatory role in DOR, enhancing the translational potential of the 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 = $249,000 )
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Biomedical Research and Research Training	000	3	8/5/2026	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $249,000

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Role of Protein N-Myristoylation in Driving DNA Damage Response

Award Number: R00GM157498

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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