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Regulation of DNA replication kinetics by BRCA2 after DNA damage

Award Number: R01CA262227
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Regulation of DNA replication kinetics by BRCA2 after DNA damage - Germline mutations in BRCA2 predispose carriers to breast, ovarian, pancreatic, and other cancers. The gene encodes a very large protein that plays critical roles in genome integrity control by promoting homologous recombination (HR)-mediated repair of DNA double strand breaks (DSBs), DNA damage-induced cell cycle checkpoint, and stability of stalled DNA replication forks, etc. Besides, BRCA2 may play a direct role in DNA replication, as its mutant cells have long been known to have the so-called radio-resistant DNA synthesis (RDS) phenotype, which reflects a defect in the intra-S phase checkpoint, a mechanism that slows down DNA replication after DNA damage presumably to allow time for DNA repair and prevent replication of damage DNA. However, the potential role of BRCA2 in DNA replication initiation or elongation has not been defined. In our preliminary studies, we found that BRCA2 interacts with an essential DNA replication factor, MCM10, and that this interaction restrains replication fork progression, promotes fork stalling and sustains origin firing after DNA damage. We hypothesize that BRCA2 regulates DNA replication kinetics after DNA damage through its interaction with MCM10 and that a dysregulation of replication kinetics after DNA damage, or intra-S phase checkpoint defect, leads to increased mutation rate, cancer development and therapy resistance. We propose 3 specific aims to test the hypotheses. In Aim 1, we will define the mechanisms of BRCA2 function in DNA replication kinetics after DNA damage. In Aim 2, we will determine the role of the BRCA2-MCM10 interaction in DNA replication fidelity and cancer cell response to DNA damaging therapies. In Aim 3, we will determine the role of BRCA2-MCM10 interaction in spontaneous and radiation-induced tumor development. Our findings and proposed studies will elucidate key mechanisms of BRCA2 function in DNA replication, provide new insights into the regulation of replication kinetics after DNA damage, and define the impact of RDS and replication kinetics dysregulation on cancer development and tumor relapse after radiation and chemotherapy.


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 = $327,533 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Cause and Prevention Research	002	4	6/14/2024	NON-COMPETING CONTINUATION	$327,533
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Cause and Prevention Research	001	3	2/16/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$55,026
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	2	2/16/2024	NON-COMPETING CONTINUATION	-$55,026
														Subtotal = $327,533

Issue Date FY: 2023 ( Subtotal = $337,877 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Cause and Prevention Research	000	3	7/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$337,877
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Cause and Prevention Research	001	2	7/10/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $337,877

Issue Date FY: 2022 ( Subtotal = $337,877 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	2	6/2/2022	NON-COMPETING CONTINUATION	$337,877
														Subtotal = $337,877

Issue Date FY: 2021 ( Subtotal = $344,772 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	1	6/24/2021	NEW	$344,772
														Subtotal = $344,772

Grand Total All Awards = $1,348,059

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Regulation of DNA replication kinetics by BRCA2 after DNA damage

Award Number: R01CA262227

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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