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Molecular and Cellular Biology, December 2005, p. 10652-10664, Vol. 25, No. 23
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.23.10652-10664.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inactivation of Ku-Mediated End Joining Suppresses mec1 Lethality by Depleting the Ribonucleotide Reductase Inhibitor Sml1 through a Pathway Controlled by Tel1 Kinase and the Mre11 Complex

Laboratoire d'Ingénierie des Systèmes Macromoléculaires, IBSM, CNRS, 31 chemin Joseph Aiguier, 13402 Marseille, Cedex 20, France,¹ Rosenstiel Center, Brandeis University, 415 South Street, Waltham, Massachusetts 02454-9110,³ Department of Molecular Medicine/IBT, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, Texas 78245²

Received 16 May 2005/ Returned for modification 9 June 2005/ Accepted 18 August 2005

RAD53 and MEC1 are essential Saccharomyces cerevisiae genes required for the DNA replication and DNA damage checkpoint responses. Their lethality can be suppressed by increasing the intracellular pool of deoxynucleotide triphosphates. We report that deletion of YKU70 or YKU80 suppresses mec1, but not rad53, lethality. We show that suppression of mec1 lethality is not due to Ku^–-associated telomeric defects but rather results from the inability of Ku^– cells to efficiently repair DNA double strand breaks by nonhomologous end joining. Consistent with these results, mec1 lethality is also suppressed by lif1, which like yku70 and yku80, prevents nonhomologous end joining. The viability of yku70 mec1 and yku80 mec1 cells depends on the ATM-related Tel1 kinase, the Mre11-Rad50-Xrs2 complex, and the DNA damage checkpoint protein Rad9. We further report that this Mec1-independent pathway converges with the Rad53/Dun1-regulated checkpoint kinase cascade and leads to the degradation of the ribonucleotide reductase inhibitor Sml1.

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