Dynamic Control of dNTP Synthesis in Early Embryos

Exponential increase of cell numbers in early embryos requires large amounts of DNA precursors (deoxyribonucleoside triphosphates (dNTPs)). Little is understood about how embryos satisfy this demand. We examined dNTP metabolism in the early Drosophila embryo, in which gastrulation is preceded by 13 sequential nuclear cleavages within only 2 hr of fertilization. Surprisingly, despite the breakneck speed at which Drosophila embryos synthesize DNA, maternally deposited dNTPs can generate less than half of the genomes needed to reach gastrulation. The rest of the dNTPs are synthesized “on the go.” The rate-limiting enzyme of dNTP synthesis, ribonucleotide reductase, is inhibited by endogenous levels of deoxyATP (dATP) present at fertilization and is activated as dATP is depleted via DNA polymerization. This feedback inhibition renders the concentration of dNTPs at gastrulation robust, with respect to large variations in maternal supplies, and is essential for normal progression of embryogenesis. •Fly embryos make dNTPs “on the go” during nuclear cleavage cycles•Embryonic dNTP synthesis is inhibited by maternally deposited dNTPs•dNTP production initiates as DNA polymerization depletes maternal stores•Negative feedback control of dNTP synthesis is essential for normal development Rapid nuclear cleavages in early Drosophila embryos require massive amounts of dNTPs. Song et al. show that embryos synthesize dNTPs “on the go.” Feedback regulation of synthesis, whereby the rate-limiting dNTP synthesis enzyme is inhibited by dATP and is reactivated with depletion of maternal dNTP supplies, is essential for development.