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Mechanisms of replication fork protection and recovery

Award Number: R01CA248526
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/12/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Mechanisms of replication fork protection and recovery - Summary During this funding period, we uncovered that the ATR signaling pathway is essential for safeguarding single- stranded (ss)-DNA gaps from being degraded by nucleases, as well as facilitating their effective repair when cancer cells undergo transient treatment with PARP inhibitors (PARPi). Moreover, we found that ssDNA gaps fail to be repaired in conditions where PARPi treatment is continuous, leading to their collision with DNA replication forks and the subsequent breaking of these forks. These broken forks are irreparable in cancer cells lacking the function of the breast cancer susceptibility genes BRCA1 and BRCA2. However, they are repaired by BRCA-proficient cells, indicating the presence of a fork recovery pathway that is absent in BRCA-deficient cells and whose absence contributes to the susceptibility of BRCA mutant cancers to PARPi. Based on these findings, we propose that the ATR signaling pathway has a previously underrecognized function in controlling the processing and repair of ssDNA gaps in cells treated with PARPi. The first aim will define the actual mechanisms by which ATR signaling limits the resection of ssDNA gaps by nucleases, as well as the mechanisms by which ATR signaling promotes the repair of gaps in cancer cells exposed to PARPi. We will achieve this goal by coupling our single-molecule DNA fiber assays with GAP-iPOND, a modified iPOND assay that we specifically developed to unbiasedly identify proteins associating with gaps in an ATR-regulated manner. Moreover, the electron microscopy approach available in Vindigni lab to directly visualize and measure the size of the ssDNA gaps on DNA replication forks provides a unique tool to study the formation, processing, and repair of ssDNA gaps. Using the same techniques, the second aim will test the innovative hypothesis that ATR, together with key recombination factors RAD51, BRCA1, and BRCA2, is also required to promote the repair of broken forks originating from ssDNA gap-replication fork collisions under conditions of continuous PARPi treatment. As tumors are exposed to PARPi repeatedly during cancer treatment, the abilities of tumor cells to repair both ssDNA gaps and broken forks are likely relavent to the therapeutic response to PARPi. Our studies will establish a new paradigm for the roles of the ATR signaling pathway and central recombination factors in the processing and repair of ssDNA gaps and broken forks in PARPi-treated cancer cells. They will also reveal how these pathways are deregulated in BRCA-deficient tumors and how their deregulation contributes to PARPi sensitivity. Interestingly, we also found that PARPi-resistant cells have fewer ssDNA gaps and DNA breaks compared to the PARPi-sensitive counterparts, and that inhibiting ATR activity restores ssDNA gap degradation and PARPi sensitivity. Thus, Aim 3 will test whether the pathways of ssDNA gap protection and fork repair are rewired in BRCA1-mutant cells when they become PARPi resistant. This knowledge is essential for a better understanding of the molecular mechanisms that dictate PARPi response in BRCA-deficient tumors and for developing new molecularly guided strategies to overcome PARPi 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: 2026 ( Subtotal = $549,653 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	7	4/27/2026	NON-COMPETING CONTINUATION	$549,653
														Subtotal = $549,653

Issue Date FY: 2025 ( Subtotal = $563,808 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	6	4/21/2025	COMPETING CONTINUATION	$563,808
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	001	5	5/13/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $563,808

Issue Date FY: 2024 ( Subtotal = $487,649 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Cause and Prevention Research	001	5	4/16/2024	NON-COMPETING CONTINUATION	$25,666
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Cause and Prevention Research	000	5	1/9/2024	NON-COMPETING CONTINUATION	$461,983
														Subtotal = $487,649

Issue Date FY: 2023 ( Subtotal = $503,050 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	4	1/30/2023	NON-COMPETING CONTINUATION	$503,050
														Subtotal = $503,050

Issue Date FY: 2022 ( Subtotal = $503,050 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	001	3	5/19/2022	NON-COMPETING CONTINUATION	$41,067
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	3	1/10/2022	NON-COMPETING CONTINUATION	$461,983
														Subtotal = $503,050

Issue Date FY: 2021 ( Subtotal = $513,314 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	2	1/25/2021	NON-COMPETING CONTINUATION	$513,314
														Subtotal = $513,314

Issue Date FY: 2020 ( Subtotal = $527,308 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	1	2/11/2020	NEW	$527,308
														Subtotal = $527,308

Grand Total All Awards = $3,647,832

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Mechanisms of replication fork protection and recovery

Award Number: R01CA248526

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/12/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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