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The concept of one-protein&#x2013;multiple-function, i.e. moonlighting proteins, is an ever-expanding paradigm. We obtained compelling evidence that an array of &#x2018;cytoplasmic&#x2019; metabolic enzymes can enter the nuclei to carry out moonlighting transcription functions; this phenomenon is conserved from Drosophila to humans. Of particular interest are the classical glycolytic enzymes GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and LDH (lactate dehydrogenase), which utilize NAD(H) as coenzymes and not only moonlight (in their nuclear forms) to regulate the transcription of S-phase-specific histone genes, but also act as metabolic/redox sensors that link histone gene switching to DNA replication and S-phase progression

Integration of the metabolic/redox state, histone gene switching, DNA replication and S-phase progression by moonlighting metabolic enzymes