Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes

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...

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Autores principales:	Rita Hirmondo, Anna Lopata, Eva Viola Suranyi, Beata G. Vertessy, Judit Toth
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bef3ef7961d0413e9b1437ec1505ae42
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spelling	oai:doaj.org-article:bef3ef7961d0413e9b1437ec1505ae422021-12-02T12:32:32ZDifferential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes10.1038/s41598-017-06206-y2045-2322https://doaj.org/article/bef3ef7961d0413e9b1437ec1505ae422017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06206-yhttps://doaj.org/toc/2045-2322Abstract 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 increased in parallel with the in vitro activity-loss of Dut accompanied with a considerable increase in the mutation rate. 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.Rita HirmondoAnna LopataEva Viola SuranyiBeata G. VertessyJudit TothNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rita Hirmondo Anna Lopata Eva Viola Suranyi Beata G. Vertessy Judit Toth Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes
description	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 increased in parallel with the in vitro activity-loss of Dut accompanied with a considerable increase in the mutation rate. 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.
format	article
author	Rita Hirmondo Anna Lopata Eva Viola Suranyi Beata G. Vertessy Judit Toth
author_facet	Rita Hirmondo Anna Lopata Eva Viola Suranyi Beata G. Vertessy Judit Toth
author_sort	Rita Hirmondo
title	Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes
title_short	Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes
title_full	Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes
title_fullStr	Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes
title_full_unstemmed	Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes
title_sort	differential control of dntp biosynthesis and genome integrity maintenance by the dutpase superfamily enzymes
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/bef3ef7961d0413e9b1437ec1505ae42
work_keys_str_mv	AT ritahirmondo differentialcontrolofdntpbiosynthesisandgenomeintegritymaintenancebythedutpasesuperfamilyenzymes AT annalopata differentialcontrolofdntpbiosynthesisandgenomeintegritymaintenancebythedutpasesuperfamilyenzymes AT evaviolasuranyi differentialcontrolofdntpbiosynthesisandgenomeintegritymaintenancebythedutpasesuperfamilyenzymes AT beatagvertessy differentialcontrolofdntpbiosynthesisandgenomeintegritymaintenancebythedutpasesuperfamilyenzymes AT judittoth differentialcontrolofdntpbiosynthesisandgenomeintegritymaintenancebythedutpasesuperfamilyenzymes
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Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes

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