Posttranslational arginylation enzyme Ate1 affects DNA mutagenesis by regulating stress response

Abstract

Arginylation is a protein posttranslational modification (PTM) which leads to addition of an extra arginine at the N‐terminus of the target proteins and peptides. This process is evolutionarily conserved, and is mediated by arginyltransferase1 (Ate1). While earlier studies found that the overall arginylation activity often increases during stressing conditions including heat shock, oxidative stress, and injury, little is known about the role of arginylation or Ate1 in stress response. Here we report that arginylation promotes growth arrest and cell death, 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 under stressing conditions such as oxidative stress, heat shock, and osmotic stresses, as well as the exposure to heavy metals or radiation. Conversely, in wild‐type cells with normal stress response, 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 that Ate1 is required to suppress mutation frequency in yeast and mammalian cells during DNA‐damaging conditions such as ultraviolet irradiation. Our data thereby explain the basis for the involvement of arginylation in physiological and diseased conditions by its regulation of cell death and/or mutagenesis. We also uncover a novel mechanism by which a posttranslational modification exerts a global effect on mutagenesis.