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The BRCA1-A complex function in DNA repair

Award Number: R01CA138835
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2009
PERIOD OF PERFORMANCE END DATE: 02/28/2031

Group Awards By:

View Award Description

The BRCA1-A complex function in DNA repair - Summary Encounters between DNA replication forks and genomic lesions invoke requirements for DNA repair by homologous recombination (HR). These events at damaged forks are important determinants of response to chemotherapeutics such as Poly(ADP)ribose polymerase and Topoisomerase I inhibitors. Cancer associated mutations in the BRCA1, BRCA2, and ATM cause hypersensitivity to replication fork damaging agents while alterations to certain DNA damage response factors can confer resistance in such DNA repair deficient cancers. We identified the BRCA1-A complex and showed that it recognizes ubiquitin chains to target BRCA1 to damage sites. Paradoxically, the BRCA1-A complex limits end resection of DNA double-strand breaks, and this specifically affects damaged replication fork responses in ATM mutated or inhibited cells. BRCA1-A complex dysfunction causes resistance to PARP or Topoisomerase I inhibitors in ATM mutated cells. The proposed research investigates the basis for these phenomena, and how BRCA1-A complex recognition of damaged replication forks prevents end resection to yield hypersensitivity to damaged replication forks. We utilize genetic, cell biology, electron microscopy, biochemical reconstitution of the BRCA1-A complex on nucleosome arrays, and genome wide approaches to test the hypothesis the BRCA1-A complex stabilizes nucleosome structure at damaged forks to exclude chromatin remodeling factors that promote nuclease dependent resection of damaged forks. Our goals are to delineate molecular events necessary for each process and understand how (1) the BRCA1-A complex recognizes damaged forks (2) the fork structures that serve as substrates for end resection in ATM mutated cells that lack the BRCA1-A complex, and (3) how chromatin remodeling mediates the increased end resection and homologous recombination observed in BRCA1-A complex deficient cells. Our studies will yield fundamental advances to the understanding cancer genome integrity control.


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 = $368,656 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	16	3/19/2026	COMPETING CONTINUATION	$368,656
														Subtotal = $368,656

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	15	7/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

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	001	8	6/8/2017	NON-COMPETING CONTINUATION	$31,751
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
														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 = $5,200,599

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The BRCA1-A complex function in DNA repair

Award Number: R01CA138835

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2009

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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