A Novel Cell Cycle Inhibitor Stalls Replication Forks and Activates S Phase Checkpoint

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

volume 6 | issue 13

1 July 2007
Pages: 1621 - 1630

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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 antiproliferative 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.