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

Vaidehi Krishnan, Léon Dirick, Hwa Lim Hong, Tiffany Siew Joo Lim, Ling Si Hoe San, Seng Cheng Chee, Lee Yap Kai, Anthony Ting, Etienne Schwob, Uttam Surana*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

DNA replication checkpoint is activated in response to replication stresses. It maintains the integrity of stalled replication forks and prevents premature segregation of largely unreplicated chromosomes. In budding yeast, Mec1 and Rad53 kinases (homologous to mammalian ATM/ATR and Chk2 kinases, respectively) are the main effectors of this checkpoint control. Using a yeast based screen, we have identified a compound (named here ENA) which inhibits DNA replication and activates Mec1/Rad53 checkpoint. A brief exposure to this compound stops fork progression at or near replication origin and renders the forks incompetent to resume replication despite the presence of a functional checkpoint. ENA also inhibits DNA synthesis in mammalian cells leading to the activation of ATM/ATR pathway and the induction of apoptosis in a p53 independent manner. Interestingly, ENA acts as an effective anti-proliferative agent against a subset of cancer cell lines and as an anti-tumor agent against human xenografts in mice. Thus, ENA is a potent cell cycle inhibitor with conceivable therapeutic potential.

Original languageEnglish (US)
Pages (from-to)1621-1630
Number of pages10
JournalCell Cycle
Volume6
Issue number13
DOIs
StatePublished - Jul 1 2007

Keywords

  • Anti-cancer compound
  • Cell cycle
  • Cell cycle inhibitor
  • Checkpoints
  • DNA replication
  • Mitosis

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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