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Ubiquitin-mediated regulation of repair pathway choice at persistent double-strand breaks in yeast

Award Number: R01GM157166
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: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Ubiquitin-mediated regulation of repair pathway choice at persistent double-strand breaks in yeast - Project Summary Genome stability is fundamentally important to human health as mutations may lead to cancer or inherited dis- ease. DNA double-strand breaks (DSBs) pose a particular hazard since incorrect repair results in chromosome rearrangements accompanied by DNA loss or gain. As such, it is particularly noteworthy that some sequences are at elevated risk for breakage or incorrect repair. One example are sequences that stimulate the erroneous addition of a telomere at an internal site following a DNA double strand break. Telomeres are repetitive se- quences that protect the ends of linear, eukaryotic chromosomes from degradation and facilitate complete rep- lication through recruitment of the enzyme telomerase. In contrast to the stabilizing role of telomeres at chromo- some ends, interstitial telomere-like sequences result in sequence loss if acted upon by telomerase to generate a new telomere. In humans, de novo telomere addition (dnTA) at genomic “hotspots” occurs in multiple diseases. Understanding why certain sequences trigger chromosome rearrangements at increased frequency is of high importance to human health. This proposal examines sequences in the budding yeast (Saccharomyces cerevisiae) that undergo dnTA at elevated frequency (Sites of Repair-associated Telomere Addition; SiRTAs). Following a double-strand break (DSB), resection of the 5’ strand at a SiRTA generates TG-rich (telomere-like) single-stranded DNA that is bound by the telomere-associated protein Cdc13. Similar to its role at endogenous telomeres, Cdc13 recruits telomer- ase to initiate new telomere synthesis. Our preliminary data demonstrate that SiRTAs more profoundly impact genome stability than previously appreciated. Loss of Ubp10, a ubiquitin protease, dramatically increases non- reciprocal translocations and large deletions at SiRTAs, some of which occur through Rad51-independent break- induced replication (BIR), a poorly understood process implicated in tumor genome instability. Genetic results argue that abnormally prolonged or extensive ubiquitylation of the yeast replicative sliding clamp (Proliferating Cell Nuclear Antigen; PCNA) in the ubp10D strain accounts for this phenotype. PCNA ubiquitylation and its downstream outcomes are highly conserved between yeast and humans, raising the significance of these ob- servations. The majority of rearrangements occur between SiRTAs and subtelomeric repetitive elements, gen- erating recombination products similar to those observed in cells that survive telomerase deficiency by alternative lengthening of telomeres (ALT), a process that contributes to cellular immortality in human cancer. Proposed work examines the mechanism through which SiRTAs stimulate rearrangements at sites of Cdc13 binding. Ex- periments will elucidate the role of PCNA-ubiquitylation in regulating repair-pathway choice at a persistent DSB and identify the cis- and trans-acting factors that support Rad51-independent BIR. This system provides a uniquely tractable model for the study of RAD51-independent BIR and early events of ALT.


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 = $342,570 )
2026	2026	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	1	5/27/2026	NEW	$342,570
														Subtotal = $342,570

Grand Total All Awards = $342,570

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Ubiquitin-mediated regulation of repair pathway choice at persistent double-strand breaks in yeast

Award Number: R01GM157166

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: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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