Friday, April 26, 2024 4/26/2024

The RAP80-BRCC36 Deubiquitinating Complex in DNA Repair

Award Number: R01CA138835
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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Contact PD/PI: Greenberg, Roger A. Summary Faithful execution of homologous recombination DNA repair is essential for genome integrity and is a critical determinant of cancer etiology and therapeutic response. This relationship is prominently exemplified by hereditary breast and ovarian cancer, which arises as a consequence of germline mutations to BRCA1 and a network of genes encoding its interacting partners. Dysfunction within this BRCA network produces hypersensitivity to poly(ADP)ribose polymerase inhibitors, which are clinically approved agents that have efficacy in the setting of BRCA mutation and homologous recombination deficiency in general. Resistance frequently occurs to these agents as a consequence of restored homologous recombination DNA repair. It is thus essential to understand how this occurs at a fundamental mechanistic level. We discovered that BRCA1 is targeted to lysine63-linked ubiquitin chromatin regions aligning DNA double-strand breaks and damaged replication forks. This localization requires BRCA1 interaction with the A-complex. This dimeric complex of five proteins includes a ubiquitin binding protein, RAP80, and a deubiquitinating enzyme, BRCC36. RAP80 and BRCC36 are specific for binding lysine63-linked ubiquitin and its hydrolysis. Deficiency of the A-complex reduces BRCA1 DNA damage localization and causes excessive end resection at replication fork damage. Interestingly, loss of the A-complex confers resistance to PARP inhibitors in genetic backgrounds where end resection is diminished. How the BRCA1-A-complex links chromatin recognition to control of end resection and therapeutic response is not currently understood. This proposal will integrate in vivo, cellular, and structure guided biochemical approaches to understand how the A-complex links DNA double-strand break ubiquitin recognition on nucleosomes to homologous recombination. To achieve these goals, we develop novel methodologies that enable us to identify the entire DNA damage response proteome on chromatin and how this affects nucleosome modifications and stability. These studies will yield fundamental advances to the understanding of genome integrity control and clarify new strategies to target underlying vulnerabilities in a broad range of malignancies. ! !


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 = $305,731 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	15	3/11/2024	NON-COMPETING CONTINUATION	$289,640
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	15	4/18/2024	NON-COMPETING CONTINUATION	$16,091
														Subtotal = $305,731

Issue Date FY: 2023 ( Subtotal = $321,821 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	14	2/20/2023	NON-COMPETING CONTINUATION	$321,821
														Subtotal = $321,821

Issue Date FY: 2022 ( Subtotal = $316,599 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	13	3/21/2022	NON-COMPETING CONTINUATION	$290,750
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	13	6/22/2022	NON-COMPETING CONTINUATION	$25,849
														Subtotal = $316,599

Issue Date FY: 2021 ( Subtotal = $331,097 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	12	3/26/2021	NON-COMPETING CONTINUATION	$331,097
														Subtotal = $331,097

Issue Date FY: 2020 ( Subtotal = $333,884 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	002	11	9/3/2020	COMPETING CONTINUATION	$22,074
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	11	3/17/2020	COMPETING CONTINUATION	$333,884
2020	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	10	9/3/2020	NON-COMPETING CONTINUATION	-$22,074
														Subtotal = $333,884

Issue Date FY: 2019 ( Subtotal = $307,982 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	10	3/14/2019	NON-COMPETING CONTINUATION	$307,982
														Subtotal = $307,982

Issue Date FY: 2018 ( Subtotal = $317,509 )
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	9	5/23/2018	NON-COMPETING CONTINUATION	$31,751
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	9	3/14/2018	NON-COMPETING CONTINUATION	$285,758
														Subtotal = $317,509

Issue Date FY: 2017 ( Subtotal = $317,509 )
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	8	3/10/2017	NON-COMPETING CONTINUATION	$285,758
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	8	6/8/2017	NON-COMPETING CONTINUATION	$31,751
														Subtotal = $317,509

Issue Date FY: 2016 ( Subtotal = $317,509 )
2016	2016	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	7	3/8/2016	NON-COMPETING CONTINUATION	$317,509
														Subtotal = $317,509

Issue Date FY: 2015 ( Subtotal = $372,509 )
2015	2015	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	6	4/15/2015	COMPETING CONTINUATION	$332,509
2015	2015	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Trans-NIH Research Support	002	6	9/10/2015	SUPPLEMENT FOR EXPANSION	$40,000
2015	2014	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	5	4/10/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $372,509

Issue Date FY: 2014 ( Subtotal = $312,379 )
2014	2014	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	5	4/17/2014	NON-COMPETING CONTINUATION	$22,542
2014	2014	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	5	12/30/2013	NON-COMPETING CONTINUATION	$289,837
														Subtotal = $312,379

Issue Date FY: 2013 ( Subtotal = $302,718 )
2013	2013	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	4	11/29/2012	NON-COMPETING CONTINUATION	$161,021
2013	2013	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	4	5/9/2013	NON-COMPETING CONTINUATION	$141,697
														Subtotal = $302,718

Issue Date FY: 2012 ( Subtotal = $322,040 )
2012	2012	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	3	11/17/2011	NON-COMPETING CONTINUATION	$289,837
2012	2012	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	3	4/19/2012	NON-COMPETING CONTINUATION	$32,203
														Subtotal = $322,040

Issue Date FY: 2011 ( Subtotal = $322,040 )
2011	2011	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	2	5/12/2011	NON-COMPETING CONTINUATION	$23,240
2011	2011	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	2	11/4/2010	NON-COMPETING CONTINUATION	$298,800
														Subtotal = $322,040

Issue Date FY: 2010 ( Subtotal = $330,616 )
2010	2010	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	1	11/30/2009	NEW	$330,616
														Subtotal = $330,616

Grand Total All Awards = $4,831,943

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The RAP80-BRCC36 Deubiquitinating Complex in DNA Repair

Award Number: R01CA138835

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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