Beta-lapachone triggers a Mre11-Tel1 dependent G1/S checkpoint in S. cerevisiae

MAURICIO ARIEL MENACHO; JOSÉ RAMÓN MURGUÍA

CELL CYCLE

LANDES BIOSCIENCE

Lugar: Austin, Texas; Año: 2006 vol. 5 p. 2509 - 2516

1538-4101

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 transi- tion, 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 treat- ment. 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 anti-tumour activity.