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The Role of Mono-ADP-Ribosylation by PARP14 in Radioresistance

Award Number: R01ES026184
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2016
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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The Role of Mono-ADP-Ribosylation by PARP14 in Radioresistance - Project Summary DNA double stranded breaks (DSBs) interfere with cellular viability, but also initiate chromosomal translocations resulting in genomic instability and promoting carcinogenesis. BRCA1 and BRCA2 proteins are essential for homologous recombination (HR)-mediated repair of DSBs. Understanding the mechanisms of the BRCA pathway has broad implications for human health. When replication forks encounter damaged DNA, they arrest and unless properly processed, they collapse leading to DNA breaks and genomic instability. To avoid their collapse, stalled forks can be reversed by annealing the two nascent strands to each other, in a process catalyzed by DNA translocases such as ZRANB3. The BRCA proteins load RAD51 on reversed forks to protect the DNA ends against degradation by the nuclease MRE11. The ability to protect forks against degradation corelates with DNA damage sensitivity. Thus, replication fork protection is essential for DNA repair and genomic stability. However, how protection of stalled replication forks against nucleolytic degradation is achieved represents a major knowledge gap. The PARP family at least 17 members, with various and lesser understood functions than the founding member PARP1. PARP14 has been associated with multiple cellular processes, but mechanistic details are generally sparse. We previously showed that PARP14 loss reduces HR efficiency and sensitizes cells to radiation. Recently, we have identified a novel role of PARP14 in promoting replication fork degradation, genomic instability and DNA damage sensitivity, which is the focus on this application. For this application, our goal is to understand how PARP14 promotes fork degradation, resulting in DNA damage sensitivity of BRCA-deficient cells. Our overall hypothesis is that PARP14 interferes with the RAD51-MRE11 mechanism of control of DNA resection at reversed replication forks to trigger nascent strand degradation, thus enhancing DNA damage sensitivity in BRCA-deficient cells. Aim 1 is to reveal the impact of PARP14 on RAD51-mediated protection of stalled replication forks. We hypothesize that PARP14 interferes with BRCA-independent stabilization of RAD51 on reversed forks, to enhance their degradation. Aim 2 is to uncover how PARP14 engages MRE11 for nucleolytic degradation of damaged forks. We hypothesize that PARP14 binds to stalled replication forks in BRCA-deficient cells and recruits MRE11 to initiate nucleolytic degradation of nascent DNA at these structures. Aim 3 is to elucidate the role of KU in fork protection against nucleolytic resection by EXO1 and MRE11. We hypothesize that KU binding to reversed forks protects them against EXO1-mediated degradation, but enables nascent strand resection by the MRE11-PARP14 complex. Since DNA damaging agents promote genomic instability by inducing nascent strand degradation, potentially underlying their carcinogenesis, successful accomplishment of these Specific Aims would reveal a new mechanism of genome stability and tumor suppression, centered on PARP14. It may also reveal PARP14 as a biomarker for the tumor response to radiation and genotoxic chemotherapy, in the context of the BRCA status.


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 = $379,533 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	9	1/6/2025	NON-COMPETING CONTINUATION	$379,533
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	001	9	1/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $379,533

Issue Date FY: 2024 ( Subtotal = $379,533 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	8	12/21/2023	NON-COMPETING CONTINUATION	$379,533
														Subtotal = $379,533

Issue Date FY: 2023 ( Subtotal = $379,533 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	001	7	1/10/2023	NON-COMPETING CONTINUATION	$379,533
2023	2020	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	5	12/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $379,533

Issue Date FY: 2022 ( Subtotal = $379,533 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	6	3/17/2022	COMPETING CONTINUATION	$379,533
														Subtotal = $379,533

Issue Date FY: 2020 ( Subtotal = $345,861 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	5	1/7/2020	NON-COMPETING CONTINUATION	$345,861
														Subtotal = $345,861

Issue Date FY: 2019 ( Subtotal = $345,946 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	4	1/7/2019	NON-COMPETING CONTINUATION	$345,946
														Subtotal = $345,946

Issue Date FY: 2018 ( Subtotal = $346,027 )
2018	2018	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	3	2/5/2018	NON-COMPETING CONTINUATION	$346,027
														Subtotal = $346,027

Issue Date FY: 2017 ( Subtotal = $340,686 )
2017	2017	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	2	2/1/2017	NON-COMPETING CONTINUATION	$340,686
														Subtotal = $340,686

Issue Date FY: 2016 ( Subtotal = $346,181 )
2016	2016	MILTON S HERSHEY MEDICAL CENTER	500 UNIVERSITY DRIVE, POB 850	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	001	1	1/20/2016	NEW	-$10,240
2016	2016	MILTON S HERSHEY MEDICAL CENTER	500 UNIVERSITY DRIVE, POB 850	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	1	1/18/2016	NEW	$356,421
														Subtotal = $346,181

Grand Total All Awards = $3,242,833

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The Role of Mono-ADP-Ribosylation by PARP14 in Radioresistance

Award Number: R01ES026184

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2016

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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