Metabolic control of replisome plasticity in genome surveillance

Metabolic pathways and DNA replication are both adaptable and essential for early development and cancer progression. While each process is well understood individually, the mechanisms coordinating them are just beginning to emerge. Nucleotide biosynthesis serves as a crucial link, with fluctuating nucleotide pools leading to imbalanced deoxyribonucleotide (dNTP) and increased ribonucleotide (rNTP) levels, impairing DNA synthesis and triggering replication stress; ultimately driving developmental disorders and cancer. To counter these challenges, the replisome - the core machinery of DNA replication - continuously adjusts its architecture and speed in response to physiological changes, including nucleotide fluctuations. This review outlines recent insights into how the replisome aligns its function with metabolic changes in nucleotide levels and explores emerging links between metabolism and genome stability, and their roles in development and disease.