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Cell Cycle 2006 Nov 12;5(21):2509-16. Epub 2006 Sep 12.

Instituto de Biología Molecular y Celular de Plantas, Universidad Politécnica de Valencia, Valencia, Spain.

Beta-lapachone is an anticancer agent that selectively induces cell death in several human cancer cells. The mechanism of beta-lapachone cytotoxicity is not yet fully understood. Here we report that beta-lapachone treatment delayed cell cycle progression at the G(1)/S transition, incremented phosphorylation of the Rad53p checkpoint kinase and decreased cell survival in the budding yeast Saccharomyces cerevisiae. Read More

DNA Repair (Amst) 2007 Feb 13;6(2):190-201. Epub 2006 Nov 13.

Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, United Kingdom.

DNA double-strand breaks (DSBs), which are generated by ionizing radiation (IR) and a range of other DNA damaging agents, are repaired by homologous recombination (HR) or non-homologous end-joining (NHEJ). Previous studies have shown that NHEJ in Saccharomyces cerevisiae requires the Yku70p-Yku80p heterodimer and a complex consisting of DNA Ligase IV, Lif1p and Nej1p. Here, we report that Nej1p is phosphorylated in response to DNA damage in a manner that relies on the DNA damage checkpoint kinases Mec1p, Rad53p and Dun1p. Read More

Mol Biol Cell 2004 Dec 29;15(12):5443-55. Epub 2004 Sep 29.

Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.

Activation of Rad53p by DNA damage plays an essential role in DNA damage checkpoint pathways. Rad53p activation requires coupling of Rad53p to Mec1p through a "mediator" protein, Rad9p or Mrc1p. We sought to determine whether the mediator requirement could be circumvented by making fusion proteins between the Mec1 binding partner Ddc2p and Rad53p. Read More

Mol Biol Cell 2004 Sep 30;15(9):4051-63. Epub 2004 Jun 30.

Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, USA.

Replication blocks and DNA damage incurred during S phase activate the S-phase and intra-S-phase checkpoint responses, respectively, regulated by the Atrp and Chk1p checkpoint kinases in metazoans. In Saccharomyces cerevisiae, these checkpoints are regulated by the Atrp homologue Mec1p and the kinase Rad53p. A conserved role of these checkpoints is to block mitotic progression until DNA replication and repair are completed. Read More

EMBO J 2004 Mar 26;23(5):1188-97. Epub 2004 Feb 26.

MRC Protein Phosphorylation Unit, Wellcome Trust Biocentre/Medical Sciences Institute, University of Dundee, Dundee DD1 5EH, UK.

The DNA damage-responsive protein kinases ATM and ATR phosphorylate SQ/TQ motifs that lie in clusters in most of their in vivo targets. Budding yeast Esc4p contains a cluster of SQ/TQ motifs, suggesting that it might be a target of Mec1p/Tel1p (yeast ATR/ATM). Here it is reported that Esc4p is phosphorylated by Mec1p in response to DNA damage during DNA replication and that cells lacking Esc4p are hypersensitive to DNA damage specifically during S phase. Read More