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

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, res...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2007-07, Vol.6 (13), p.1621-1630
Main Authors: Krishnan, Vaidehi, Dirick, Léon, Lim, Hong Hwa, Lim, Tiffany Siew Joo, Si-Hoe, San Ling, Cheng, Chee Seng, Yap, Kai Lee, Ting, Anthony, Schwob, Etienne, Surana, Uttam
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents
Antineoplastic Agents - pharmacology
Ataxia Telangiectasia Mutated Proteins
Binding
Biology
Bioscience
Calcium
Cancer
Cell
Cell Cycle
Cell Cycle - drug effects
Cell Cycle Proteins
Cell Cycle Proteins - metabolism
Cell Proliferation
Cell Proliferation - drug effects
Cell Survival
Cell Survival - drug effects
Cells, Cultured
Cycle
DNA
DNA - metabolism
DNA Replication
DNA Replication - drug effects
DNA-Binding Proteins
DNA-Binding Proteins - metabolism
Drug Evaluation, Preclinical
Epoxy Compounds
Epoxy Compounds - pharmacology
Genes, cdc
Genes, cdc - drug effects
HCT116 Cells
HeLa Cells
Humans
Landes
Life Sciences
Mice
Mice, Nude
Models, Biological
Naphthalimides
Naphthalimides - pharmacology
Organogenesis
Protein-Serine-Threonine Kinases
Protein-Serine-Threonine Kinases - metabolism
Proteins
S Phase
S Phase - drug effects
Tumor Suppressor Proteins
Tumor Suppressor Proteins - metabolism
Vegetal Biology
Xenograft Model Antitumor Assays
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Description
Summary: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 acompound (named here ENA) which inhibits DNA replication and activatesMec1/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.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.6.13.4373