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The role of NUDT16 in DNA damage response and tumorigenesis

Award Number: R01CA222195
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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The role of NUDT16 in DNA damage response and tumorigenesis - Project Summary The DNA damage-signaling pathways play critical roles in maintaining genomic stability following DNA damage. Disruption of these pathways leads to genomic instability and increased cancer incidence, suggesting that these pathways are essential for the prevention of neoplastic transformation. Our recent work demonstrated that NUDT16’s catalytic hydrolase activity is required for 53BP1 de-ADP-ribosylation, 53BP1 protein stability, and its function in cell survival. An important question remains of whether other critical unidentified substrate proteins exist for NUDT16 hydrolase activity. Our preliminary data revealed that NUDT16 loss decreased the level of multiple DNA damage checkpoint and repair protein. Moreover, cells lacking NUDT16 showed significant DNA repair defects and chromosomal aberrations. In addition, Nudt16-/- mice presents increased spleen weight and elevated number of splenic follicles. Driven by these promising preliminary results, in this renewal application, we hypothesize that NUDT16, through its catalytic activity, regulates multiple DNA damage checkpoint and repair proteins, to facilitate DNA end resection-initiated HR repair, which is critical for the maintenance of genomic stability and prevention of tumorigenesis. We will pursue the following Specific Aims: Aim 1: Determine the role(s) of NUDT16 in regulation of the DNA repair pathways. Aim 2: Define the physiological function of Nudt16 in vivo. Aim 3: Investigate the underlying mechanisms by which Nudt16 loss contributes to lymphomagenesis in mice. Taken together, these in-depth studies focused on NUDT16 not only contribute significantly to our understanding of the complex regulation of DNA repair pathways but may also provide critical insights into the underlying mechanisms by which loss of Nudt16 contributes to tumorigenesis in mice.


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 = $405,116 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	001	7	7/30/2025	NON-COMPETING CONTINUATION	$405,116
2025	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	000	5	3/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $405,116

Issue Date FY: 2024 ( Subtotal = $405,116 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	001	6	8/6/2024	COMPETING CONTINUATION	$405,116
2024	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	000	5	7/30/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $405,116

Issue Date FY: 2023 ( Subtotal = $360,922 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	000	5	11/8/2022	NON-COMPETING CONTINUATION	$331,459
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	001	5	3/21/2023	NON-COMPETING CONTINUATION	$29,463
														Subtotal = $360,922

Issue Date FY: 2022 ( Subtotal = $360,922 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	001	4	5/24/2022	NON-COMPETING CONTINUATION	$29,463
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	000	4	11/30/2021	NON-COMPETING CONTINUATION	$331,459
														Subtotal = $360,922

Issue Date FY: 2021 ( Subtotal = $368,288 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	000	3	11/6/2020	NON-COMPETING CONTINUATION	$349,873
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	001	3	1/22/2021	NON-COMPETING CONTINUATION	$18,415
														Subtotal = $368,288

Issue Date FY: 2020 ( Subtotal = $366,954 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	001	2	1/15/2020	NON-COMPETING CONTINUATION	$36,697
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	000	2	11/6/2019	NON-COMPETING CONTINUATION	$330,257
														Subtotal = $366,954

Issue Date FY: 2019 ( Subtotal = $366,000 )
2019	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	000	1	11/1/2018	NEW	$366,000
														Subtotal = $366,000

Grand Total All Awards = $2,633,318

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The role of NUDT16 in DNA damage response and tumorigenesis

Award Number: R01CA222195

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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