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, 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.
Krishnan
Vaidehi
V
Institute of Molecular and Cell Biology, Proteos, Singapore.
Dirick
Léon
L
Lim
Hong Hwa
HH
Lim
Tiffany Siew Joo
TS
Si-Hoe
San Ling
SL
Cheng
Chee Seng
CS
Yap
Kai Lee
KL
Ting
Anthony
A
Schwob
Etienne
E
Surana
Uttam
U
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004852:Epoxy Compounds / Q000494:pharmacology*; D018816:Genes, cdc / Q000187:drug effects; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D053644:Naphthalimides / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016196:S Phase / Q000187:drug effects*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C522420:2-methyl-1,8-epoxynaphthalimide; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004852:Epoxy Compounds; D053644:Naphthalimides; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases