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Molecular and Cellular Biology, December 2005, p. 10273-10285, Vol. 25, No. 23
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.23.10273-10285.2005

Loss of SOD1 and LYS7 Sensitizes Saccharomyces cerevisiae to Hydroxyurea and DNA Damage Agents and Downregulates MEC1 Pathway Effectors{dagger}

Carole D. Carter, Lauren E. Kitchen, Wei-Chun Au, Christopher M. Babic, and Munira A. Basrai*

Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, National Naval Medical Center, Building 8, Room 5101, 8901 Wisconsin Avenue, Bethesda, Maryland 20889-5105

Received 26 January 2005/ Returned for modification 18 March 2005/ Accepted 13 September 2005

Aerobic metabolism produces reactive oxygen species, including superoxide anions, which cause DNA damage unless removed by scavengers such as superoxide dismutases. We show that loss of the Cu,Zn-dependent superoxide dismutase, SOD1, or its copper chaperone, LYS7, confers oxygen-dependent sensitivity to replication arrest and DNA damage in Saccharomyces cerevisiae. We also find that sod1{Delta} strains, and to a lesser extent lys7{Delta} strains, when arrested with hydroxyurea (HU) show reduced induction of the MEC1 pathway effector Rnr3p and of Hug1p. The HU sensitivity of sod1{Delta} and lys7{Delta} strains is suppressed by overexpression of TKL1, a transketolase that generates NADPH, which balances redox in the cell and is required for ribonucleotide reductase activity. Our results suggest that the MEC1 pathway in sod1{Delta} mutant strains is sensitive to the altered cellular redox state due to increased superoxide anions and establish a new relationship between SOD1, LYS7, and the MEC1-mediated checkpoint response to replication arrest and DNA damage in S. cerevisiae.

* Corresponding author. Mailing address: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, National Naval Medical Center, Building 8, Room 5101, 8901 Wisconsin Ave., Bethesda, MD 20889-5105. Phone: (301) 402-2552. Fax: (301) 480-0380. E-mail: basraim{at}mail.nih.gov.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org.

Molecular and Cellular Biology, December 2005, p. 10273-10285, Vol. 25, No. 23
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.23.10273-10285.2005




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