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Spontaneous replication fork collapse regulates telomere length homeostasis in wild type yeast

Award Number: R01GM142173
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: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Spontaneous replication fork collapse regulates telomere length homeostasis in wild type yeast - Project Summary/Abstract: Telomeres present unique challenges for genomes with linear chromosomes, including the inability of the semi-conservative DNA replication machinery to fully duplicate the ends of linear molecules. This is solved in virtually all eukaryotes by the enzyme telomerase, through the addition of telomeric repeats onto chromosome ends. It is widely assumed that the primary site of action for telomerase is the single-stranded G-rich overhang at the ends of chromosomes, formed after DNA replication is complete. A newly developed assay that monitors spontaneous monitor fork collapse at an interstitial telomeric tract has demonstrated there is a second substrate for telomerase in wild type yeast, which is a collapsed fork generated during replication of duplex telomeric DNA. Newly collapsed forks are extensively elongated by telomerase in a single cell division, indicating that a major source of newly synthesized telomeric repeats in wild type cells occurs at collapsed forks. Furthermore, the ability of telomerase to elongate newly collapsed forks is dependent on fork remodeling proteins. In parallel, a re-examination of the role of a telomere-dedicated RPA-like complex (t- RPA) in budding yeast argues that this complex facilitates lagging strand synthesis during duplex DNA replication, rather than protecting telomeres in from unregulated resection. Additional data argues that this complex collaborates with the canonical RPA complex to stabilize replication forks during duplex telomeric DNA replication. Collectively, these observations provide a substantial challenge to current models for how telomere homeostasis is maintained in wild type yeast. This application tests the model that the activity of telomerase in response to spontaneous fork collapse is a major determinant of telomere length regulation. Aim 1 will test the hypothesis that telomerase activity at newly collapsed forks proceeds through a regulatory pathway distinct from how telomerase engages fully replicated chromosome termini. Aim 2 will test the hypothesis that two RPA complexes, one dedicated to the leading strand (RPA) and the other (t-RPA) bound to the lagging strand, collaborate to promote stabilization of the fork during replication of duplex telomeric DNA. The third Aim will examine a new role for the canonical RPA complex in regulating telomerase, through surfaces that are highly conserved from yeast to humans.


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: 2024 ( Subtotal = $380,000 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	4	7/11/2024	NON-COMPETING CONTINUATION	$38,000
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	1/5/2024	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $380,000

Issue Date FY: 2023 ( Subtotal = $380,000 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	3	1/5/2023	NON-COMPETING CONTINUATION	$342,000
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	002	3	3/28/2023	NON-COMPETING CONTINUATION	$38,000
2023	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	10/24/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $380,000

Issue Date FY: 2022 ( Subtotal = $380,000 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	2	6/23/2022	NON-COMPETING CONTINUATION	$38,000
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	1/11/2022	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $380,000

Issue Date FY: 2021 ( Subtotal = $380,000 )
2021	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	3/12/2021	NEW	$380,000
														Subtotal = $380,000

Grand Total All Awards = $1,520,000

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Spontaneous replication fork collapse regulates telomere length homeostasis in wild type yeast

Award Number: R01GM142173

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: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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