Exploring ATM/ATR Signaling at the Crossroads of DNA Repair and Mechano-transduction

Gene defects in DNA repair pathways represent a significant cause of inherited neurological disease. Though traditionally viewed as nuclear regulators of the DNA damage response (DDR), ATM and ATR also function in the cytoplasm, influencing the actin cytoskeleton and mechanical stress signaling. Mutations in cytoskeletal proteins can mimic DDR-related syndromes, suggesting a functional link between DNA repair and mechano-transduction. The Mech-ATM project investigates how ATM/ATR signaling integrates mechanical cues from the extracellular matrix (ECM) with genomic stability mechanisms, aiming to identify key phosphorylation targets within cytoskeletal networks and define how disruptions in tGene defects in the DNA repair pathway represent a significant cause of inherited neurological disease. Though traditionally viewed as nuclear regulators of the DNA damage response (DDR), ATM and ATR also function in the cytoplasm, influencing the actin cytoskeleton and mechanical stress signaling. Mutations in cytoskeletal proteins can mimic DDR-related syndromes, suggesting a functional link between DNA repair and mechano-transduction. The Mech-ATM project investigates how ATM/ATR signaling integrates mechanical cues from the extracellular matrix (ECM) with genomic stability mechanisms, aiming to identify key phosphorylation targets within cytoskeletal networks and define how disruptions of this pathway affect brain development. Recent findings implicate ECM stiffness as a modulator of cellular behavior, and environmental factors like microplastics may exacerbate mechanical dysregulation and DNA damage, particularly in genetically susceptible individuals. Using cerebral organoids and proteomic approaches, Mech-ATM will uncover how ATM/ATR-dependent mechano-transduction contributes to neurodevelopment. This work may reveal novel therapeutic targets for neurodevelopmental and neurodegenerative diseases, while highlighting the impact of environmental stressors on brain health.