# Project 4: Fork Repair: Mechanisms and consequences of stalled replication fork processing

> **NIH NIH P01** · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · 2023 · $380,881

## Abstract

SUMMARY- PROJECT 4 - Fork Repair: Mechanisms and consequences of stalled replication fork
processing
DNA replication is central to cancer etiology and treatment since errors during replication generate most cancer
driver mutations, and many cancer treatments including PARP inhibitors and chemotherapeutic agents target
DNA replication. We aim to discover the mechanisms of replication-coupled DNA repair and tolerance that are
important for tumorigenesis and development of new therapeutics. The premise of this application is that ATP-
dependent motor proteins act in pathways to control replication fork remodeling as a mechanism of replication
stress tolerance and error avoidance. In order to overcome challenge, intermediates in these pathways are
shunted towards alternative mechanisms, including translesion synthesis and repriming. The mechanism
deployed may depend on the type of challenge, its persistence, and the inactivation of selected replication stress
response and repair proteins that are common in cancer. While ensuring replication is completed, the use of
error-prone mechanisms can generate the genetic alterations that drive tumor development and drug resistance.
This genetic instability may also provide new opportunities for therapeutic intervention through synthetic lethal
approaches. This project will answer fundamental questions about these replication stress response
mechanisms using a combination of structural, biochemical, genetic, and cell biology approaches. Specifically,
we will determine how ATP-dependent fork reversal enzymes control replication fork dynamics, identify the
mechanisms that regulate replication stress tolerance pathways, and determine the consequences of damage
tolerance and fork repair pathways for genome stability. These aims will be accomplished by the combined efforts
of four investigators with expertise in cell biology, genetics, biochemistry, biophysics, and structural biology and
a history of working in cooperation with each other and with the other project investigators and research cores.

## Key facts

- **NIH application ID:** 10695050
- **Project number:** 5P01CA092584-23
- **Recipient organization:** UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
- **Principal Investigator:** David K Cortez
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $380,881
- **Award type:** 5
- **Project period:** 2001-09-27 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695050

## Citation

> US National Institutes of Health, RePORTER application 10695050, Project 4: Fork Repair: Mechanisms and consequences of stalled replication fork processing (5P01CA092584-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10695050. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*