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DNA double-strand break chromatin alterations and genome integrity

Award Number: R01GM101149
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: 06/01/2013
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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DNA double-strand break chromatin alterations and genome integrity - Contact PD/PI: Greenberg, Roger A. Summary Evolutionary conserved DNA repair mechanisms cooperate throughout the cell cycle to faithfully maintain genome integrity. However, a minimal understanding exists for how damaged chromatin directs the series of events that dictate ensuing repair mechanism. This gap in knowledge is particularly relevant to a poorly understood homology directed repair mechanism that becomes active to maintain telomere length in approximately 15% of human cancers. Alternative lengthening of telomeres (ALT) occurs by noncanonical homology directed DNA repair mechanism in cancers of mesenchymal origin. The recombination mechanisms responsible for telomere maintenance represent a unique vulnerability in ALT reliant cancers. We have developed experimental systems that enable quantitative, real-time visualization of each step in the homology directed repair of damaged telomeres. Our published studies reveal that ALT is initiated by DNA damage dependent homology directed repair synthesis that proceeds unidirectionally to the end of the chromosome. We named this mechanism Break Induced Telomere Synthesis and showed that it is critical for telomere lengthening in cells that utilize ALT. Here, we examine the question of how DNA damage responses assemble on telomeric chromatin to direct long-tract homology directed repair telomere synthesis. We hypothesize that Break Induced Telomere Synthesis occurs by assembling elements of several different DNA repair mechanisms on telomeric chromatin to achieve homology directed repair synthesis. Our unpublished results definitively support this premise, showing extensive PCNA- ubiquitination and recruitment of the 5’-3’ nuclease SNM1A and 5’-3’ helicase FANCJ at damaged telomeres to promote DNA repair synthesis and telomere integrity. We will investigate the basis for their damage dependent association with telomeres and functions in recombination dependent repair synthesis at telomeres using a multifaceted approach that allows us to examine each step of the telomere damage response in cells and in vitro in highly purified systems that assemble the break induced replisome on defined substrates. These fundamental studies are designed to understand the critical elements of Break Induced Telomere Synthesis and how it allows telomere lengthening for sustained proliferation in cells that rely on 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: 2025 ( Subtotal = $295,495 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	12	3/25/2025	NON-COMPETING CONTINUATION	$295,495
														Subtotal = $295,495

Issue Date FY: 2024 ( Subtotal = $328,328 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	11	7/23/2024	NON-COMPETING CONTINUATION	$32,833
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	11	3/25/2024	NON-COMPETING CONTINUATION	$295,495
														Subtotal = $328,328

Issue Date FY: 2023 ( Subtotal = $474,981 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	10	7/20/2023	SUPPLEMENT FOR EXPANSION	$140,428
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	10	3/7/2023	NON-COMPETING CONTINUATION	$334,553
														Subtotal = $474,981

Issue Date FY: 2022 ( Subtotal = $334,749 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	9	5/31/2022	COMPETING CONTINUATION	$334,749
2022	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	8	8/28/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $334,749

Issue Date FY: 2020 ( Subtotal = $322,000 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	8	3/5/2020	NON-COMPETING CONTINUATION	$322,000
														Subtotal = $322,000

Issue Date FY: 2019 ( Subtotal = $322,000 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	7	3/13/2019	NON-COMPETING CONTINUATION	$322,000
														Subtotal = $322,000

Issue Date FY: 2018 ( Subtotal = $322,000 )
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	6	3/26/2018	NON-COMPETING CONTINUATION	$289,800
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	6	6/5/2018	NON-COMPETING CONTINUATION	$32,200
														Subtotal = $322,000

Issue Date FY: 2017 ( Subtotal = $322,000 )
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	003	5	9/9/2017	COMPETING CONTINUATION	$61,519
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	5	5/8/2017	COMPETING CONTINUATION	$322,000
2017	2016	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	5/3/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
2017	2016	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	002	4	9/9/2017	EXTENSION WITH OR WITHOUT FUNDS	-$61,519
														Subtotal = $322,000

Issue Date FY: 2016 ( Subtotal = $304,000 )
2016	2016	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	3/29/2016	EXTENSION WITH OR WITHOUT FUNDS	$304,000
														Subtotal = $304,000

Issue Date FY: 2015 ( Subtotal = $304,000 )
2015	2015	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	3/27/2015	NON-COMPETING CONTINUATION	$304,000
														Subtotal = $304,000

Issue Date FY: 2014 ( Subtotal = $304,000 )
2014	2014	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	3/10/2014	NON-COMPETING CONTINUATION	$304,000
														Subtotal = $304,000

Issue Date FY: 2013 ( Subtotal = $304,000 )
2013	2013	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	5/24/2013	NEW	$304,000
														Subtotal = $304,000

Grand Total All Awards = $3,937,553

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DNA double-strand break chromatin alterations and genome integrity

Award Number: R01GM101149

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: 06/01/2013

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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