ATM mediates adaptive epigenetic responses to mitochondrial stress (961.1)

Reactive oxygen species (ROS) are important signaling molecules that regulate numerous cellular processes. In contrast to their historic association with disease and accelerated aging, evidence in humans and model organisms suggests that ROS signaling can promote health and extend lifespan, yet ROS signaling pathways remain relatively unknown. We recently demonstrated that a mitochondrial ROS (mtROS) signal extends lifespan of the budding yeast Saccharomyces cerevisiae by activating conserved DNA damage response kinases that inactivate a jumonji‐family histone demethylase specifically at subtelomeric regions and repress gene expression. Here, we present evidence that this pathway is conserved in mammals. The DNA damage response kinase ATM, which dimerizes following ROS‐induced disulfide bond formation, also senses mtROS. Formation of the ATM dimer correlates with increased levels of H3K9me3, a histone modification characteristic of heterochromatin formation. Increased H3K9me3 following mtROS signaling is ATM‐dependent, and is associated with repressed telomeric and subtelomeric gene expression. Experiments are in progress to examine the role of jumonji‐family histone demethylases in the mammalian response to mtROS signaling. These results indicate that mtROS signaling via DNA damage response kinases and mtROS‐dependent subtelomeric heterochromatin formation are conserved from yeast to human and expand on the important roles of ATM in redox homeostasis, telomere regulation, and the DNA damage response. Grant Funding Source : NIH F31AG043242‐01