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Post-translational Modifications in DNA Damage Response: a Structural Perspective

Award Number: R01CA132878
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2008
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Post-translational Modifications in DNA Damage Response: a Structural Perspective - Project Summary/Abstract This application is focused on probing how post-translational modifications (PTMs) contribute to the DNA damage response (DDR), a vital process for the maintenance of genomic integrity. The long-term goal is a basic mechanistic understanding of DNA damage repair that will facilitate the development of new therapeutic strategies to combat cancer. In this context, the proposed overall objective is to elucidate how the tumor suppressor E3 ubiquitin ligase BRCA1-BARD1 and DDR protein 53BP1 regulate the cell cycle dependency of DNA double-strand break (DSB) repair pathway selection. BRCA1-BARD1 promotes DSB repair by homologous recombination (HR) during S and G2 phases of the cell cycle whereas 53BP1 inactivates HR and promotes repair by non-homologous end-joining (NHEJ) mostly in G1 phase. Imbalance between HR and NHEJ—for example linked to mutations in BRCA1-BARD1—can result in chromosomal rearrangements that drive oncogenesis. BRCA1-BARD1 and 53BP1 can recognize a similar DSB-dependent PTM, the ubiquitylation of histone H2A at K15 in the nucleosome, the basic subunit of chromatin, suggesting that competition for chromatin association in response to DNA damage could account, at least in part, for the antagonistic activities of BRCA1- BARD1 and 53BP1 with respect to HR. The central hypothesis to be tested is that BRCA1-BARD1, through its ubiquitin ligase activity on the nucleosome, indirectly leads to 53BP1 displacement from damaged chromatin and directly prevents the establishment in newly replicated chromatin of a PTM (i.e., dimethylation of histone H4 K20) required for the chromatin recruitment of 53BP1. The rationale for this work is that it will provide fundamental knowledge about the mechanisms of action of BRCA1-BARD1 and 53BP1. Such knowledge is important for understanding how DSBs are repaired with implications for cancer prevention and the development of new therapies. Two specific aims will be pursued to test the central hypothesis. Aim 1: Probe how BRCA1-BARD1 associates with and modifies chromatin in response to DNA damage. Aim 2: Probe how 53BP1 associates with chromatin and is antagonized by BRCA1-BARD1. In both aims, structural biology approaches will be integrated to characterize BRCA1-BARD1, 53BP1 and a chromatin remodeler that may connect BRCA1-BARD1 and 53BP1 functionally. The structures will inform functional in vitro studies and collaborative cell biology to reveal the chromatin recruitment mechanisms of BRCA1-BARD1 and 53BP1. The proposed research is significant because it is expected to explain how BRCA1-BARD1 opposes the chromatin recruitment and retention of 53BP1 to promote HR DSB repair post-replication. This work will therefore explain how BRCA1-BARD1 and 53BP1 regulate DSB repair pathway selection in a cell cycle-dependent manner. Knowledge gained from this research is expected to stimulate the long-term development of new therapies to treat cancer.


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 = $363,150 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	13	12/30/2025	NON-COMPETING CONTINUATION	$363,150
														Subtotal = $363,150

Issue Date FY: 2025 ( Subtotal = $403,500 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	12	1/13/2025	NON-COMPETING CONTINUATION	$363,150
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	001	12	2/13/2025	NON-COMPETING CONTINUATION	$0
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	002	12	6/9/2025	NON-COMPETING CONTINUATION	$40,350
														Subtotal = $403,500

Issue Date FY: 2024 ( Subtotal = $403,500 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	11	12/19/2023	COMPETING CONTINUATION	$403,500
														Subtotal = $403,500

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2018	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	10	11/3/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	10	11/13/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $357,750 )
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	10	11/17/2017	NON-COMPETING CONTINUATION	$321,975
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	001	10	5/23/2018	NON-COMPETING CONTINUATION	$35,775
														Subtotal = $357,750

Issue Date FY: 2017 ( Subtotal = $357,750 )
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	9	11/17/2016	NON-COMPETING CONTINUATION	$321,975
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	001	9	6/7/2017	NON-COMPETING CONTINUATION	$35,775
														Subtotal = $357,750

Issue Date FY: 2016 ( Subtotal = $357,750 )
2016	2016	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	8	11/10/2015	NON-COMPETING CONTINUATION	$321,975
2016	2016	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	001	8	2/18/2016	NON-COMPETING CONTINUATION	$35,775
														Subtotal = $357,750

Issue Date FY: 2015 ( Subtotal = $357,750 )
2015	2015	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	7	11/17/2014	NON-COMPETING CONTINUATION	$321,975
2015	2015	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	001	7	1/28/2015	NON-COMPETING CONTINUATION	$35,775
														Subtotal = $357,750

Issue Date FY: 2014 ( Subtotal = $357,750 )
2014	2014	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	001	6	6/10/2014	COMPETING CONTINUATION	$37,723
2014	2014	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	6	12/26/2013	COMPETING CONTINUATION	$320,027
														Subtotal = $357,750

Issue Date FY: 2012 ( Subtotal = $304,127 )
2012	2012	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	5	3/15/2012	NON-COMPETING CONTINUATION	$304,127
														Subtotal = $304,127

Issue Date FY: 2011 ( Subtotal = $304,127 )
2011	2011	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	4	1/11/2011	NON-COMPETING CONTINUATION	$282,179
2011	2011	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	001	4	5/13/2011	NON-COMPETING CONTINUATION	$21,948
														Subtotal = $304,127

Issue Date FY: 2010 ( Subtotal = $313,533 )
2010	2010	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	3	1/21/2010	NON-COMPETING CONTINUATION	$313,533
														Subtotal = $313,533

Issue Date FY: 2009 ( Subtotal = $313,533 )
2009	2009	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	000	2	1/15/2009	NON-COMPETING CONTINUATION	$282,180
2009	2009	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Cause and Prevention Research	001	2	3/20/2009	NON-COMPETING CONTINUATION	$31,353
														Subtotal = $313,533

Issue Date FY: 2008 ( Subtotal = $313,533 )
2008	2008	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Cancer Cause and Prevention Research	000	1	3/14/2008	NEW	$313,533
														Subtotal = $313,533

Grand Total All Awards = $4,507,753

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Post-translational Modifications in DNA Damage Response: a Structural Perspective

Award Number: R01CA132878

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2008

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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