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Investigating the chromatin landscape of ALT telomeres

Award Number: F30CA298520
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2025
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Investigating the chromatin landscape of ALT telomeres - PROJECT SUMMARY/ABSTRACT Cancer cells must initiate a telomere maintenance mechanism to continuously proliferate. While the majority of tumors (85%) reactivate telomerase, a subset (15%) employs homologous recombination in a process termed alternative lengthening of telomeres (ALT). ALT primarily manifests in tumors originating from mesenchymal tissues and is characterized by long and heterogeneous telomeres, the presence of extrachromosomal telomeric repeats, localization of telomeres in nuclear PML bodies, and telomere sister chromatid exchanges. Chromatin dynamics play a crucial role in ALT; loss of chromatin remodeler ATRX is almost always observed in ALT cells, and exogenous expression of ATRX suppress ALT. However, ATRX is a large multifunctional protein, and the mechanism by which it suppresses ALT remains elusive. Furthermore, H3K9 methylation at telomeres has been implicated in promoting ALT phenotypes, and loss of H3K9 methylation represses ALT phenotypes. How H3K9 methylation regulates ALT is also unknown. I hypothesize that ATRX loss promotes ALT induction by disrupting its role in histone variant H3.3 deposition at telomeres. Further, I hypothesize that loss of H3.3 disturbs the H3K9 methylation balance at the telomeres, leading to increased H3K9 methylation, R-loop stabilization, replication stress, and double-stranded breaks driving ALT homologous recombination. The goal of this proposal is to investigate the chromatin landscape at ALT telomeres and elucidate its impact on ALT through two distinct but related objectives. In Aim 1, I will focus on the role of ATRX in ALT suppression. I will employ a base editing screen to create mutations spanning the coding sequence of ATRX. Using this screen, I will identify ATRX domains and functions that suppress ALT. In Aim 2, I will study the effect of H3K9 methylation on ALT by manipulating H3K9 methylation specifically at the telomeres. I will then assess ALT phenotypes and explore the mechanism behind H3K9 methylation’s impact on ALT with a focus on R-loop stabilization. This work will provide novel insight into how the chromatin state governs ALT and offer potential avenues to target ALT for cancer therapeutics. I am an MD/PhD student at the Weill Cornell/Memorial Sloan Kettering/Rockefeller Tri-Institutional Program, performing the proposed research in the laboratory of Dr. Agnel Sfeir at Memorial Sloan Kettering Cancer Center (MSKCC). My long-term goal is to become a physician scientist who balances patient care with running an independent research program at an academic institution. The plan outlined in this proposal, along with the support and mentorship provided by Dr. Sfeir, my thesis research committee, and the Tri-Institutional administrative faculty will help me achieve my career goals.


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 = $55,114 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Research Manpower	001	2	4/16/2026	NON-COMPETING CONTINUATION	$576
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Research Manpower	000	2	2/2/2026	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $55,114

Issue Date FY: 2025 ( Subtotal = $54,538 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Research Manpower	001	1	2/19/2025	NEW	$0
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Research Manpower	000	1	2/19/2025	NEW	$53,974
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Research Manpower	002	1	6/4/2025	NEW	$564
														Subtotal = $54,538

Grand Total All Awards = $109,652

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Investigating the chromatin landscape of ALT telomeres

Award Number: F30CA298520

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2025

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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