# Elucidating mechanisms underlying replication checkpoint control

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $474,447

## Abstract

PROJECT SUMMARY
The maintenance of genomic integrity after DNA damage and replication stress depends on the coordination of
DNA repair and cell cycle checkpoints. The replication checkpoint pathway, which comprises two critical
protein kinases, ATR and CHK1, has an essential role in this coordination. Inhibition of the replication
checkpoint results in cell lethality in response to replication stress induced by oncogenes, radiation, or
chemotherapeutic agents. Indeed, several replication checkpoint inhibitors are being tested in clinical trials as
potential anticancer agents. Our objective in this application is to provide a detailed mechanistic understanding
of replication checkpoint control, which may help us develop the best strategies for using these checkpoint
inhibitors in cancer therapy.
 We have studied replication checkpoint control for many years. We demonstrated that the ATR-dependent
replication checkpoint can be activated by a variety of DNA lesions. In addition, ATR not only activates CHK1
but also phosphorylates many other substrates, including MCM, H2AX, and others at or near stalled replication
forks to initiate replication checkpoint signaling. Moreover, we have identified and studied several key proteins
such as TOPBP1, ETAA1, and Claspin involved in replication checkpoint control.
 Many key proteins involved in DNA replication and replication checkpoint control are essential for cell
survival. Thus, it remains challenging to fully understand the roles of DNA replication and replication
checkpoint proteins in cell cycle progression. Toward this end, we recently took advantage of the dTAG-
mediated protein degradation system and established cell lines with inducible degradation of several essential
DNA replication and replication checkpoint proteins. Initial analyses of events following the depletion of these
essential proteins revealed some unexpected observations, which led us to re-evaluate replication checkpoint
control and the mechanisms underlying cell cycle transitions.
 In this project, we will determine the essential functions of these DNA replication and checkpoint proteins in
S phase and cell cycle progression. We anticipate that results from these studies will provide a better
understanding of replication checkpoint control, especially how DNA replication and replication checkpoint are
coordinated to ensure S phase progression and cell survival.

## Key facts

- **NIH application ID:** 10869938
- **Project number:** 5R01CA278758-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Junjie Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $474,447
- **Award type:** 5
- **Project period:** 2023-06-16 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869938

## Citation

> US National Institutes of Health, RePORTER application 10869938, Elucidating mechanisms underlying replication checkpoint control (5R01CA278758-02). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/10869938. Licensed CC0.

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