Cross-Talk between Carbon Metabolism and the DNA Damage Response in S. cerevisiae.
Yeast cells with DNA damage avoid respiration, presumably because products of oxidative metabolism can be harmful to DNA. We show that DNA damage inhibits the activity of the Snf1 (AMP-activated) protein kinase (AMPK), which activates expression of genes required for respiration. Glucose and DNA damage upregulate SUMOylation of Snf1, catalyzed by the SUMO E3 ligase Mms21, which inhibits SNF1 activity. The DNA damage checkpoint kinases Mec1/ATR and Tel1/ATM, as well as the nutrient-sensing protein kinase A (PKA), regulate Mms21 activity toward Snf1. Mec1 and Tel1 are required for two SNF1-regulated processes-glucose sensing and ADH2 gene expression-even without exogenous genotoxic stress. Our results imply that inhibition of Snf1 by SUMOylation is a mechanism by which cells lower their respiration in response to DNA damage. This raises the possibility that activation of DNA damage checkpoint mechanisms could contribute to aerobic fermentation (Warburg effect), a hallmark of cancer cells.
University of Colorado School of Medicine, Department of Biochemistry and Molecular Genetics, 12801 E 17(th) Avenue, Aurora, CO 80045, USA; Tel Aviv University, Department of Molecular Microbiology and Biotechnology, Haim Levanon Street, Tel Aviv 6997801, Israel. Electronic address: kobisimpsonlavy@gmail.com.
Kobi J
KJ
Simpson-Lavy
Tel Aviv University, Department of Molecular Microbiology and Biotechnology, Haim Levanon Street, Tel Aviv 6997801, Israel.
Alex
A
Bronstein
Tel Aviv University, Department of Molecular Microbiology and Biotechnology, Haim Levanon Street, Tel Aviv 6997801, Israel.
Martin
M
Kupiec
University of Colorado School of Medicine, Department of Biochemistry and Molecular Genetics, 12801 E 17(th) Avenue, Aurora, CO 80045, USA. Electronic address: mark.johnston@ucdenver.edu.
Mark
M
Johnston
D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation
D047908:Intracellular Signaling Peptides and Proteins; C500948:Mms21 protein, S cerevisiae; D025842:SUMO-1 Protein; D029701:Saccharomyces cerevisiae Proteins; C071570:SNF1-related protein kinases; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C513623:TEL1 protein, S cerevisiae; D017868:Cyclic AMP-Dependent Protein Kinases