Dynamic control of nucleotide metabolism in physiology and disease

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Abstract
Nucleotides are essential for life, serving not only as the building blocks of the genome but also as cellular energy providers, metabolic cofactors and signalling molecules. To sustain cellular function and proliferation, cells must continuously generate, recycle and precisely balance nucleotide pools in response to fluctuating metabolic and environmental demands. Nucleotide metabolism is therefore not a static biosynthetic pathway, but a dynamic system tightly integrated with cell signalling and physiology. Here we highlight the regulatory logic of nucleotide metabolism, from acute post-translational regulation to transcriptional scaling, feedback control and higher-order spatial organization into multi-enzyme assemblies and filaments. Through the lens of human genetic disorders and cancer, we examine how nucleotide depletion, pool imbalance or intermediate toxicity produce striking tissue-selective pathologies. Together, these principles position nucleotide metabolism as a central regulatory axis linking cellular metabolism, signalling and fate in health and disease.
Funding Information
  • National Institute of General Medical Sciences (R01GM143236)
  • National Cancer Institute (1R01CA289251)
  • American Cancer Society (RSG-22-177-01-TBE)
  • Cancer Prevention and Research Institute of Texas (RP210041)

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