Posttranslational arginylation enzyme Ate1 affects DNA mutagenesis by regulating stress response.
Arginyltransferase 1 (Ate1) mediates protein arginylation, a poorly understood protein posttranslational modification (PTM) in eukaryotic cells. Previous evidence suggest a potential involvement of arginylation in stress response and this PTM was traditionally considered anti-apoptotic based on the studies of individual substrates. However, here we found that arginylation promotes cell death and/or growth arrest, depending on the nature and intensity of the stressing factor. Specifically, in yeast, mouse and human cells, deletion or downregulation of the ATE1 gene disrupts typical stress responses by bypassing growth arrest and suppressing cell death events in the presence of disease-related stressing factors, including oxidative, heat, and osmotic stresses, as well as the exposure to heavy metals or radiation. Conversely, in wild-type cells responding to stress, there is an increase of cellular Ate1 protein level and arginylation activity. Furthermore, the increase of Ate1 protein directly promotes cell death in a manner dependent on its arginylation activity. Finally, we found Ate1 to be required to suppress mutation frequency in yeast and mammalian cells during DNA-damaging conditions such as ultraviolet irradiation. Our study clarifies the role of Ate1/arginylation in stress response and provides a new mechanism to explain the link between Ate1 and a variety of diseases including cancer. This is also the first example that the modulation of the global level of a PTM is capable of affecting DNA mutagenesis.
Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
Akhilesh
A
Kumar
Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
Michael D
MD
Birnbaum
Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
Devang M
DM
Patel
Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
William M
WM
Morgan
Department of Medicine, Division of Cardiology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
Jayanti
J
Singh
Department of Neurology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.|Department of Biochemistry and Molecular Biology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
Antoni
A
Barrientos
Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.|Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
Fangliang
F
Zhang
D019881:Aminoacyltransferases / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001483:Base Sequence; D016923:Cell Death; D002470:Cell Survival / Q000528:radiation effects; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051379:Mice; D016296:Mutagenesis / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013312:Stress, Physiological; D014466:Ultraviolet Rays; D015854:Up-Regulation
D029701:Saccharomyces cerevisiae Proteins; D004247:DNA; D001120:Arginine; D019881:Aminoacyltransferases; C000623203:Ate1 protein, S cerevisiae; C000623204:Ate1 protein, mouse; C019727:arginyltransferase
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