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Mechanisms underlying chromosome specific telomere lengths in yeast

Award Number: R01GM152471
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: 12/11/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Mechanisms underlying chromosome specific telomere lengths in yeast - Project Summary/Abstract Telomere length plays a pivotal role in cancer and age-related degenerative disease. Telomeres are made of simple tandem repeats, added by the enzyme telomerase, to establish a length distribution. A mechanistic understanding of the forces that regulate telomere length is needed to develop approaches to disease. Current models for how the telomere length equilibrium is maintained suggest that ends with fewer telomere repeats are more frequently elongated than ends with many repeats implying that all telomeres are regulated around the same length distribution. We developed a nanopore sequencing method to measure telomere length in yeast at the nucleotide level. Surprisingly, we found that each telomere had a distinct length distribution that was maintained over hundreds of cell divisions. This discovery requires that current models for length regulation be revised. In this proposal we detail specific experiments to test mechanisms that may modify the length distribution at specific chromosome ends: 1. Subtelomeric sequences 2. Telomere transcription/telomere RNA (TERRA), and the Sir2/3/4 histone modification complex. We will use computational approaches to determine if specific sequence motifs are associated with long or short telomeres, and we will systematically delete DNA binding sites to test their role. We will use nanopore RNA sequencing to study the long non-coding RNA TERRA, and test whether the RNA, or the action of transcribing the telomere play a role in end-specific telomere lengths. Finally, we will test the role of the histone deacetylase Sir2 and the interaction of Sir4 with Ku in determining end-specific telomere lengths. These experiments will implicate or rule out the specific factors that establish different length distributions. Understanding molecular mechanism(s) that influence telomere length distributions will set the stage to specifically manipulate telomere length. Because mechanisms of telomere length regulation are conserved across species, our experiments will set the stage for approaches to alter telomere length to treat human disease.


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 = $461,353 )
2025	2025	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Biomedical Research and Research Training	000	2	11/26/2024	NON-COMPETING CONTINUATION	$461,353
														Subtotal = $461,353

Issue Date FY: 2024 ( Subtotal = $510,150 )
2024	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Biomedical Research and Research Training	000	1	12/11/2023	NEW	$510,150
														Subtotal = $510,150

Grand Total All Awards = $971,503

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Mechanisms underlying chromosome specific telomere lengths in yeast

Award Number: R01GM152471

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: 12/11/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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