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Mechanisms of DNA Double-strand Break End Resection and Repair Pathway Choice

Award Number: R01ES007061
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/1995
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Mechanisms of DNA Double-strand Break End Resection and Repair Pathway Choice - ABSTRACT DNA double strand breaks (DSBs) are induced by environmental and chemotherapeutic agents, and during encounters of the DNA replication machinery with DNA damage. The two major, mechanistically distinct DSB repair pathways are non-homologous DNA end joining (NHEJ) and homology-directed repair (HDR). NHEJ is efficient but error-prone, while HDR is inherently accurate and represents the preferred repair tool for DNA replication-associated DSBs. HDR commences with the resection of the 5’-terminated strand at break ends to generate a DNA tail that serves as the template for assembly of the RAD51 recombinase filament. DSB repair pathway choice is linked to cell cycle progression and is determined by whether or not a DSB undergoes extensive resection. Long-range resection is principally mediated by the 5’-3’ exonuclease EXO1 or the BLM helicase-DNA2 endonuclease. The chromatin reader 53BP1 nucleates the formation of a higher order ensemble that harbors the RIF1 protein and the hetero-tetrameric Shieldin complex at DSB ends to block end resection in the G1 phase of the cell cycle. The restrictive action of the 53BP1 axis is alleviated by BRCA1- BARD1 in S and G2 phases via mechanisms that are poorly understood. Thus, BRCA1-deficient tumors, on account of their HDR-deficiency, are particularly vulnerable to PARP inhibitors (PARPi) due to synthetic lethality. However, dysfunction in the 53BP1 axis leads to HDR restoration and PARPi resistance. Importantly, we now have compelling evidence that RIF1 and Shieldin strongly restrict the activity of the DNA end resection enzymes. To elucidate the underpinnings of the DNA end resection restriction circuitry, we will employ a combinatorial approach encompassing reconstitution biochemistry and cell biology to: (1) Delineate how RIF1 and Shieldin interfere with the activity of the 5’-3’ exonuclease EXO1 and of the helicase-endonuclease complex BLM-DNA2 in DNA end resection and (2) Interrogate BRCA1-BARD1 for its ability to overcome the restriction of DNA end resection imposed by RIF1 and Shieldin. Our studies will elucidate the intricate regulatory networks that control DNA end resection onset and efficiency. Our endeavors will not only illuminate the mechanistic principles of DSB repair pathway choice, but will also exert a major impact in our understanding of how failure to properly process DSBs lead to neoplastic cell transformation and cancer, and will provide actionable information to help guide the development of targeted cancer therapies to treat BRCA- deficient cancers and circumvent drug resistance.


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 = $557,024 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	000	31	12/13/2024	NON-COMPETING CONTINUATION	$505,540
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	001	31	12/16/2024	SUPPLEMENT FOR EXPANSION	$51,484
														Subtotal = $557,024

Issue Date FY: 2024 ( Subtotal = $525,698 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	001	30	8/8/2024	SUPPLEMENT FOR EXPANSION	$20,158
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	000	30	12/14/2023	NON-COMPETING CONTINUATION	$505,540
2024	2020	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	002	28	9/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $525,698

Issue Date FY: 2023 ( Subtotal = $505,540 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	001	29	3/8/2023	COMPETING CONTINUATION	$505,540
2023	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	000	28	2/28/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $505,540

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	000	28	4/11/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $376,875 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	000	28	5/11/2020	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $376,875

Issue Date FY: 2019 ( Subtotal = $376,875 )
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	004	27	5/24/2019	NON-COMPETING CONTINUATION	$376,875
2019	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Environmental Health	000	25	3/19/2019	NON-COMPETING CONTINUATION	-$164,077
2019	2018	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	001	26	3/20/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$164,077
2019	2018	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	006	26	9/24/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$9,925
2019	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Environmental Health	005	25	9/24/2019	NON-COMPETING CONTINUATION	-$9,925
2019	2018	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Environmental Health	002	26	5/14/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$14,077
2019	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Environmental Health	003	25	5/15/2019	NON-COMPETING CONTINUATION	$14,077
														Subtotal = $376,875

Issue Date FY: 2018 ( Subtotal = $376,875 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Environmental Health	000	25	5/28/2018	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $376,875

Issue Date FY: 2017 ( Subtotal = $376,875 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Environmental Health	000	24	5/24/2017	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $376,875

Issue Date FY: 2016 ( Subtotal = $376,688 )
2016	2016	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	000	23	5/20/2016	COMPETING CONTINUATION	$376,688
														Subtotal = $376,688

Issue Date FY: 2014 ( Subtotal = $390,711 )
2014	2014	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	000	22	3/21/2014	NON-COMPETING CONTINUATION	$390,711
														Subtotal = $390,711

Issue Date FY: 2013 ( Subtotal = $387,126 )
2013	2013	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	001	21	7/9/2013	NON-COMPETING CONTINUATION	$31,605
2013	2013	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	000	21	4/10/2013	NON-COMPETING CONTINUATION	$355,521
														Subtotal = $387,126

Issue Date FY: 2012 ( Subtotal = $395,353 )
2012	2012	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	000	20	3/26/2012	NON-COMPETING CONTINUATION	$395,353
														Subtotal = $395,353

Issue Date FY: 2011 ( Subtotal = $395,143 )
2011	2011	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	001	19	6/3/2011	NON-COMPETING CONTINUATION	$24,237
2011	2011	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	000	19	3/21/2011	NON-COMPETING CONTINUATION	$370,906
														Subtotal = $395,143

Issue Date FY: 2010 ( Subtotal = $400,116 )
2010	2010	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	000	18	8/9/2010	COMPETING CONTINUATION	$400,116
														Subtotal = $400,116

Issue Date FY: 2009 ( Subtotal = $360,827 )
2009	2009	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	000	17	6/25/2009	NON-COMPETING CONTINUATION	$360,827
														Subtotal = $360,827

Issue Date FY: 2008 ( Subtotal = $360,827 )
2008	2008	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	000	16	6/17/2008	NON-COMPETING CONTINUATION	$360,827
														Subtotal = $360,827

Issue Date FY: 2007 ( Subtotal = $368,191 )
2007	2007	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	000	15	6/21/2007	NON-COMPETING CONTINUATION	$368,191
														Subtotal = $368,191

Issue Date FY: 2006 ( Subtotal = $379,188 )
2006	2006	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	000	14	6/27/2006	NON-COMPETING CONTINUATION	$379,188
														Subtotal = $379,188

Issue Date FY: 2005 ( Subtotal = $388,313 )
2005	2005	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Environmental Health	000	13	5/2/2005	COMPETING CONTINUATION	$388,313
														Subtotal = $388,313

Grand Total All Awards = $9,220,925

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Mechanisms of DNA Double-strand Break End Resection and Repair Pathway Choice

Award Number: R01ES007061

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/1995

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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