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β-lapachone Activates a Mre11p-Tel1p G1/S Checkpoint in Budding Yeast
Mauricio Menacho-Márquez and José R Murguía
volume 5 | issue 21
1 november 2006Pages: 2509 - 2516
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β-lapachone is an anticancer agent that selectively induces cell death in several human cancer cells. The mechanism of β-lapachone cytotoxicity is not yet fully understood. Here we report that β-lapachone treatment delayed cell cycle progression at the G1/S transition, incremented phosphorylation of the Rad53p checkpoint kinase and decreased cell survival in the budding yeast Saccharomyces cerevisiae. Furthermore, β-lapachone induced phosphorylation of histone H2A at serine 129. These checkpoint responses were regulated by Mec1p and Tel1p kinases. Mec1p was required for Rad53p/histone H2A phosphorylation and cell survival following β-lapachone treatment in asynchronous cultures, but not for the G1 delay. The tel1Δ mutation increased sensitivity to β-lapachone in a mec1 defective strain and compromised checkpoint responses in G1. Both Rad53p phosphorylation and G1 delay were fully dependent on a functional Mre11p-Rad50p-Xrs2p (XMR) complex, and mutants in the XMR complex were hypersensitive to β-lapachone treatment. Finally, XRS2 and TEL1 worked epistatically regarding β-lapachone sensitivity and Xrs2p was phosphorylated in a Tel1p dependent-manner after β-lapachone treatment. Taken together, these findings indicate that β-lapachone activates a Mre11p-Tel1p checkpoint pathway in budding yeast. Given the conserved nature of the Mre11p-Tel1p pathway, these results suggest that activation of the Mre11-Tel1p checkpoint could be of significance for β-lapachone antitumour activity.
Authors
Mauricio Menacho-Márquez
Instituto de Biologa0020Molecular y Celular de Plantas, Universidad Politc006eica de Valencia, Valencia, SPAIN
José R Murguía
Instituto de Biología Molecular y Celular de Plantas, Universidad Politécnica de Valencia, Valencia, SPAIN
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.