Loss of ATM Positively Regulates Rac1 Activity and Cellular Migration Through Oxidative Stress

Abstract

Ataxia‐telangiectasia mutated (ATM) is a serine‐threonine kinase that is integral in the response to DNA double‐stranded breaks (DSBs). Cells and tissues lacking ATM are prone to tumor development and enhanced tumor cell migration and invasion. Interestingly, ATM‐deficient cells exhibit high levels of oxidative stress; however, the direct mechanism whereby ATM‐associated oxidative stress may contribute to the cancer phenotype remains largely unexplored. Rac1, a member of the Rho family of GTPases, also plays an important regulatory role in cellular growth, motility, and cancer formation. Rac1 can be activated directly by reactive oxygen species (ROS), by a mechanism distinct from canonical guanine nucleotide exchange factor‐driven activation. Here we show that loss of ATM kinase activity elevates intracellular ROS, leading to Rac1 activation. Rac1 activity drives cytoskeletal rearrangements resulting in increased cellular spreading and motility. Rac1 siRNA or treatment with the ROS scavenger N‐acetyl cysteine restores wild‐type migration. These studies demonstrate a novel mechanism whereby ATM activity and ROS generation regulates Rac1 to modulate pro‐migratory cellular behavior.Support or Funding InformationThis work was funded by High Point University's Research and Sponsored Programs (MCS), the Summer Undergraduate Research Program in the Sciences (MVB, MCS), and Undergraduate Research and Creative Works (AS, MVB, MCS).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.