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

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $371,713

## Abstract

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 insight...

## Key facts

- **NIH application ID:** 10798160
- **Project number:** 5R01CA181671-07
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jieya Shao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $371,713
- **Award type:** 5
- **Project period:** 2016-12-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798160

## Citation

> US National Institutes of Health, RePORTER application 10798160, Role of nuclear profilin-1 in DNA replication fork stability and cancer chemotherapy response (5R01CA181671-07). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10798160. Licensed CC0.

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