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Structural Cell Biology of DNA Repair Machines

Award Number: P01CA092584
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/27/2001
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Structural Cell Biology of DNA Repair Machines - SUMMARY DNA repair maintains genome stability to prevent cancer and provides resistance to cancer treatments; yet, DNA repair defects lead to cancer-causing mutations and are an Achilles heel for cancer-targeted treatments. Structural Cell Biology of DNA Repair Machines 5 (SBDR-5) coordinates leaders in DNA repair (DR) to work together synergistically for comprehensive mechanistic and structural knowledge of DR processes. Four interacting Projects (P1-4) target DR pathways implicated in cancer etiology, treatment, and resistance: P1 investigates repair of base lesions from chemotherapy including a paradigm-shifting model for RNA damage responses to alkylating agents. P2 defines inter-locking pathways for repair of dsDNA breaks (DSBs), a result of radiation therapy as well as replication encounters with DNA lesions. P3 examines PARylation-mediated phase condensates and their impacts on DR for PARP inhibitor therapies. P4 determines mechanisms in replication fork stress responses, key consequences of many cancer treatments. Our highest priorities are to solve actionable structures in each Project and apply our teamwork to biochemically and biologically test molecular insights and hypotheses based on our structures. Two experimental Cores will enable efficient preparation of DR assemblies and determination of their structures. Removing bottlenecks within individual laboratories and promoting collaborative efforts, SBDR Projects and Cores together enable a comprehensive cross-pathway knowledge of dynamic multi-functional DR machines – knowledge best achieved through multi-disciplinary approaches and concerted efforts by multiple groups. Our four Program aims are: 1) Determine actionable and biologically-validated structures of DR complexes, interfaces, and conformations. 2) Dissect multi-functionality of DR machineries tested by structure-based design of separation-of-function mutations and chemical inhibitors to inform on predicted therapeutic sensitivity and development of resistance. 3) Define DR pathway interactions and crosstalk with replication dynamics to delineate DR pathway outcomes. 4) Discover synthetic lethality from mutations or chemical agents that target specific DR activities and which become essential only in conjunction with another DR defect to promote successful therapeutic interventions. SBDR will provide lasting structure-based knowledge for interpretation of mutations from The Cancer Genome Atlas and of mechanisms that inform system level knockout and knockdown correlations. Through concerted efforts, SBDR-5 will establish biologically-validated structures and synthetic lethality relationships with durable biological and medical utility. We will share constructs, mutants, inhibitors, data, and technologies to enhance synergy, reproducibility, and efficiency. Our target structures and mechanisms are both challenging and timely: the expected results will have indelible impacts on ongoing NIH research in other labs, on assessment of cancer genome data, and on knowledge for treatment strategies in ongoing clinical and preclinical trials of DR inhibitors.


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 = $2,894,273 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF CALIFORNIA	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	000	24	8/28/2024	NON-COMPETING CONTINUATION	$2,894,273
														Subtotal = $2,894,273

Issue Date FY: 2023 ( Subtotal = $3,046,580 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	001	23	8/22/2023	NON-COMPETING CONTINUATION	$2,985,648
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	002	23	9/15/2023	NON-COMPETING CONTINUATION	$60,932
2023	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	000	22	10/17/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $3,046,580

Issue Date FY: 2022 ( Subtotal = $2,985,088 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	003	22	9/1/2022	NON-COMPETING CONTINUATION	$2,985,088
2022	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	002	21	5/13/2022	COMPETING CONTINUATION	$222,726
2022	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	000	20	5/11/2022	NON-COMPETING CONTINUATION	$0
2022	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	001	20	5/13/2022	NON-COMPETING CONTINUATION	-$222,726
														Subtotal = $2,985,088

Issue Date FY: 2021 ( Subtotal = $3,043,574 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	001	21	9/21/2021	COMPETING CONTINUATION	$3,043,574
2021	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	000	20	9/14/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $3,043,574

Issue Date FY: 2020 ( Subtotal = $3,378,955 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	001	20	8/24/2020	NON-COMPETING CONTINUATION	$3,378,955
2020	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	000	19	2/11/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $3,378,955

Issue Date FY: 2019 ( Subtotal = $3,408,092 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	001	19	9/19/2019	SUPPLEMENT FOR EXPANSION	$472,585
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	000	19	8/27/2019	NON-COMPETING CONTINUATION	$2,935,507
														Subtotal = $3,408,092

Issue Date FY: 2018 ( Subtotal = $3,082,620 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	000	18	8/29/2018	NON-COMPETING CONTINUATION	$3,082,620
														Subtotal = $3,082,620

Issue Date FY: 2017 ( Subtotal = $3,275,439 )
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	002	17	8/23/2017	NON-COMPETING CONTINUATION	$3,086,387
2017	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	003	16	9/21/2017	COMPETING CONTINUATION	$189,052
2017	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	001	16	3/21/2017	COMPETING CONTINUATION	$87,312
2017	2015	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Cause and Prevention Research	000	15	3/21/2017	NON-COMPETING CONTINUATION	-$87,312
														Subtotal = $3,275,439

Issue Date FY: 2016 ( Subtotal = $2,896,480 )
2016	2016	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cancer Cause and Prevention Research	001	16	9/13/2016	COMPETING CONTINUATION	$2,896,480
2016	2015	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cancer Cause and Prevention Research	000	15	9/8/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,896,480

Issue Date FY: 2015 ( Subtotal = $2,939,283 )
2015	2015	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cancer Cause and Prevention Research	000	15	8/24/2015	NON-COMPETING CONTINUATION	$2,939,283
														Subtotal = $2,939,283

Issue Date FY: 2014 ( Subtotal = $2,865,942 )
2014	2014	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cancer Cause and Prevention Research	000	14	8/19/2014	NON-COMPETING CONTINUATION	$2,865,942
														Subtotal = $2,865,942

Issue Date FY: 2013 ( Subtotal = $2,808,109 )
2013	2013	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cancer Cause and Prevention Research	000	13	8/29/2013	NON-COMPETING CONTINUATION	$2,808,109
														Subtotal = $2,808,109

Issue Date FY: 2012 ( Subtotal = $3,001,735 )
2012	2012	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cancer Cause and Prevention Research	000	12	9/10/2012	NON-COMPETING CONTINUATION	$3,001,735
														Subtotal = $3,001,735

Issue Date FY: 2011 ( Subtotal = $2,981,000 )
2011	2011	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cancer Cause and Prevention Research	001	11	9/14/2011	COMPETING CONTINUATION	$2,981,000
2011	2010	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cancer Cause and Prevention Research	000	10	9/14/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,981,000

Issue Date FY: 2010 ( Subtotal = $3,827,727 )
2010	2010	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cancer Cause and Prevention Research	000	10	8/31/2010	NON-COMPETING CONTINUATION	$3,827,727
														Subtotal = $3,827,727

Issue Date FY: 2009 ( Subtotal = $3,728,432 )
2009	2009	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cancer Cause and Prevention Research	000	9	8/28/2009	NON-COMPETING CONTINUATION	$3,728,432
														Subtotal = $3,728,432

Issue Date FY: 2008 ( Subtotal = $3,587,003 )
2008	2008	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cancer Cause and Prevention Research	000	8	9/2/2008	NON-COMPETING CONTINUATION	$3,587,003
														Subtotal = $3,587,003

Issue Date FY: 2007 ( Subtotal = $3,341,614 )
2007	2007	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cancer Cause and Prevention Research	000	7	9/7/2007	NON-COMPETING CONTINUATION	$3,341,614
														Subtotal = $3,341,614

Issue Date FY: 2006 ( Subtotal = $3,300,000 ) (Continued on the next page)
Grand Total All Awards = $79,263,063

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Structural Cell Biology of DNA Repair Machines

Award Number: P01CA092584

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/27/2001

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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