A novel cell cycle inhibitor stalls replication forks and activates S phase checkpoint

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Updated: Jul 14, 2026

Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
12:02

Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols

Published on: June 6, 2017

Vaidehi Krishnan1, Léon Dirick, Hong Hwa Lim

  • 1Institute of Molecular and Cell Biology, Proteos, Singapore.

Cell Cycle (Georgetown, Tex.)
|July 3, 2007
PubMed

Insights

A novel compound, ENA, inhibits DNA replication and activates cell cycle checkpoints in yeast and human cells. This DNA replication inhibitor shows anti-proliferative and anti-tumor effects, suggesting therapeutic potential.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The DNA replication checkpoint safeguards genome integrity during replication stress.
  • Key kinases Mec1/Rad53 (yeast) and ATM/ATR/Chk2 (mammalian) mediate checkpoint responses.
  • Understanding replication stress response is crucial for cancer therapy.

Purpose of the Study:

  • To identify novel inhibitors of DNA replication.
  • To investigate the mechanism of action of a newly identified compound, ENA.
  • To evaluate the therapeutic potential of ENA in cancer models.

Main Methods:

  • Yeast-based genetic screening to identify replication inhibitors.
  • Biochemical assays to assess DNA synthesis inhibition and checkpoint activation.
  • Cell-based assays in mammalian cells to study ATM/ATR pathway activation and apoptosis.
  • In vivo studies using human xenograft models in mice.

Main Results:

  • A compound, ENA, was identified that inhibits DNA replication and activates the Mec1/Rad53 checkpoint in yeast.
  • ENA halts replication fork progression and prevents fork restart.
  • ENA inhibits DNA synthesis in mammalian cells, activates ATM/ATR, induces p53-independent apoptosis, and exhibits anti-proliferative and anti-tumor activity.

Conclusions:

  • ENA is a potent inhibitor of DNA replication and cell cycle progression.
  • ENA activates DNA replication checkpoints and induces apoptosis through the ATM/ATR pathway.
  • ENA demonstrates significant anti-cancer potential, warranting further investigation for therapeutic applications.

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