Metabolism and DNA replication are the two most fundamental biological functions in life. The catabolic branch of metabolism breaks down nutrients to produce energy and precursors used by the anabolic branch of metabolism to synthesize macromolecules. DNA replication consumes energy and precursors for faithfully copying genomes, propagating the genetic material from generation to generation. We have exquisite understanding of the mechanisms that underpin and regulate these two biological functions. However, the molecular mechanism coordinating replication to metabolism and its biological function remains mostly unknown. Understanding how and why living organisms respond to fluctuating nutritional stimuli through cell-cycle dynamic changes and reproducibly and distinctly temporalize DNA synthesis in a wide-range of growth conditions is important, with wider implications across all domains of life. After summarizing the seminal studies that founded the concept of the metabolic control of replication, we review data linking metabolism to replication from bacteria to humans. Molecular insights underpinning these links are then presented to propose that the metabolic control of replication uses signalling systems gearing metabolome homeostasis to orchestrate replication temporalization. The remarkable replication phenotypes found in mutants of this control highlight its importance in replication regulation and potentially genetic stability and tumorigenesis.
Keywords: DNA replication; allosteric regulation; cell cycle; central carbon metabolism; moonlighting functions; signalling.