Differential control of dNTP biosynthesis and genome integrity maintenance by dUTPases

Hirmondó, Rita and Lopata, Anna and Surányi, Éva Viola and Vértessy G., Beáta and Tóth, Judit (2017) Differential control of dNTP biosynthesis and genome integrity maintenance by dUTPases. SCIENTIFIC REPORTS, 7. No. 6043. ISSN 2045-2322

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Abstract

dUTPase superfamily enzymes generate dUMP, the obligate precursor for de novo dTTP biosynthesis, from either dUTP (monofunctional dUTPase, Dut) or dCTP (bifunctional dCTP deaminase/dUTPase, Dcd:dut). In addition, the elimination of dUTP by these enzymes prevents harmful uracil incorporation into DNA. These two beneficial outcomes have been thought to be related. Here we determined the relationship between dTTP biosynthesis (dTTP/dCTP balance) and the prevention of DNA uracilation in a mycobacterial model that encodes both the Dut and Dcd:dut enzymes, and has no other ways to produce dUMP. We show that, in dut mutant¬¬¬¬¬ mycobacteria, the dTTP/dCTP balance remained unchanged, but the uracil content of DNA and the mutation rate increased in parallel with the in vitro activity-loss of Dut. Conversely, dcd:dut inactivation resulted in perturbed dTTP/dCTP balance and two-fold increased mutation rate, but did not increase the uracil content of DNA. Thus, unexpectedly, the regulation of dNTP balance and the prevention of DNA uracilation are decoupled and separately brought about by the Dcd:dut and Dut enzymes, respectively. Available evidence suggests that the discovered functional separation is conserved in humans and other organisms.

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