Metabolic Rewiring in the Face of Genomic Assault: Integrating DNA Damage Response and Cellular Metabolism.

The DNA damage response (DDR) and cellular metabolism exhibit a complex, bidirectional relationship crucial for maintaining genomic integrity. Studies across multiple organisms, from yeast to humans, have revealed how cells rewire their metabolism in response to DNA damage, supporting repair processes and cellular homeostasis. We discuss immediate metabolic shifts upon damage detection and long-term reprogramming for sustained genomic stability, highlighting key signaling pathways and participating molecules. Importantly, we examine how DNA repair processes can conversely induce metabolic changes and oxidative stress through specific mechanisms, including the histone H2A variant X (H2AX)/ataxia telangiectasia mutated (ATM)/NADPH oxidase 1 (Nox1) pathway and repair-specific ROS signatures. The review covers organelle-specific responses and metabolic adaptations associated with different DNA repair mechanisms, with a primary focus on human cells. We explore the implications of this DDR-metabolism crosstalk in cancer, aging, and neurodegenerative diseases, and discuss emerging therapeutic opportunities. By integrating recent findings, this review provides a comprehensive overview of the intricate interplay between DDR and cellular metabolism, offering new perspectives on cellular resilience and potential avenues for therapeutic intervention.