Tuesday, July 1, 2025 7/1/2025

Role of nuclear profilin-1 in DNA replication fork stability and cancer chemotherapy response

Award Number: R01CA181671
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2016
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Role of nuclear profilin-1 in DNA replication fork stability and cancer chemotherapy response - PROJECT SUMMARY DNA replication stress is one of the mechanistic underpinnings of many genotoxic chemotherapies which cause replication fork stalling. Stalled forks frequently reverse to form four-way junction structures, as a natural coping mechanism, to allow repair of the DNA lesions ahead of the forks and avoid catastrophic fork collapse. However, fork reversal is a double-edged sword because the nascent DNA in the reversed arm is susceptible to excessive nuclease resection if not securely protected which can lead to severe genome instability. Many factors play tug- of-war at stalled forks to strengthen or weaken their stability, and their balance in the cell determines the fate of replication forks during stress and cellular outcome upon chemotherapy treatments. In this study, we investigate the molecular mechanisms of a novel replication fork regulator named profilin-1 (Pfn1). As a well-known actin- binding protein, Pfn1 plays an essential role in actin polymerization and dynamics. Paradoxically, it also has well- documented but poorly understood anticancer activities including the ability to sensitize cancer cells to chemotherapy treatments. In recently published work, we demonstrated for the first time that the anticancer effects of Pfn1 stem, at least partially, from its nuclear functions that are spatially and mechanistically distinct from its cytoplasmic function in actin regulation. We showed that nuclear Pfn1 directly interacts with ENL in the Super Elongation Complex (SEC) and inhibits the ability of SEC to drive transcriptional elongation of various cancer genes including MYC. We also presented clinical evidence that nuclear Pfn1 level is frequently decreased in cancer due to the upregulation of its nuclear exporter exportin-6 (XPO6), whose deletion increases nuclear Pfn1 level and decreases tumor growth. These findings establish the notion that Pfn1 has fundamentally important and cancer-relevant functions in the nucleus, and set the stage for further discovery of its involvement in additional nuclear processes. In this grant, we present novel evidence that nuclear Pfn1 promotes normal DNA replication but causes fork destabilization during stress and increases cellular sensitivity to replication stress- inducing chemotherapies including PARP inhibitors. We hypothesize that nuclear Pfn1 has context-dependent effects on DNA replication forks. Under normal conditions, it promotes fork progression by increasing chromatin relaxation through SNF2H. Under stressed conditions, it promotes fork reversal by stimulating SNF2H and increases fork resection by suppressing BOD1L, leading to fork destabilization. Aim 1: Determine the effect of nuclear Pfn1 on BOD1L-dependent replication fork protection. Aim 2: Define the role of Pfn1/SNF2H axis in replication fork remodeling and stability. Aim 3: Understand the chemotherapy-sensitizing ability of nuclear Pfn1. Work proposed in this grant has the potential to generate important mechanistic insights and proof-of-concept therapeutic data rationalizing further investigation of nuclear Pfn1 as a synthetic lethal target for genotoxic chemotherapies.


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 = $352,150 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	8	2/19/2025	NON-COMPETING CONTINUATION	$352,150
														Subtotal = $352,150

Issue Date FY: 2024 ( Subtotal = $371,713 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Cause and Prevention Research	003	7	4/17/2024	NON-COMPETING CONTINUATION	$19,563
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Cause and Prevention Research	002	7	3/6/2024	NON-COMPETING CONTINUATION	$352,150
2024	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	001	6	11/16/2023	COMPETING CONTINUATION	$726
2024	2021	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	5	11/16/2023	NON-COMPETING CONTINUATION	-$726
														Subtotal = $371,713

Issue Date FY: 2023 ( Subtotal = $392,954 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	6	3/1/2023	COMPETING CONTINUATION	$392,954
														Subtotal = $392,954

Issue Date FY: 2021 ( Subtotal = $348,844 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	001	5	1/25/2021	NON-COMPETING CONTINUATION	$17,443
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	5	11/17/2020	NON-COMPETING CONTINUATION	$331,401
														Subtotal = $348,844

Issue Date FY: 2020 ( Subtotal = $348,844 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	001	4	1/31/2020	NON-COMPETING CONTINUATION	$34,885
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	4	11/25/2019	NON-COMPETING CONTINUATION	$313,959
														Subtotal = $348,844

Issue Date FY: 2019 ( Subtotal = $338,378 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	3	11/27/2018	NON-COMPETING CONTINUATION	$338,378
														Subtotal = $338,378

Issue Date FY: 2018 ( Subtotal = $348,844 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	2	11/20/2017	NON-COMPETING CONTINUATION	$313,959
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	001	2	5/23/2018	NON-COMPETING CONTINUATION	$34,885
														Subtotal = $348,844

Issue Date FY: 2017 ( Subtotal = $348,844 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	1	11/25/2016	NEW	$348,844
														Subtotal = $348,844

Grand Total All Awards = $2,850,571

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Role of nuclear profilin-1 in DNA replication fork stability and cancer chemotherapy response

Award Number: R01CA181671

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2016

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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