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De novo dNTP production is essential for normal postnatal murine heart development
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. (Andrei Chabes)
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. (Paulina Wanrooij)
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). (Andrei Chabes)
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2019 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, article id jbc.RA119.009492Article in journal (Refereed) Epub ahead of print
Abstract [en]

The building blocks of DNA, dNTPs, can be produced de novo or can be salvaged from deoxyribonucleosides. However, to what extent the absence of de novo dNTP production can be compensated for by the salvage pathway is unknown. Here, we eliminated de novo dNTP synthesis in the mouse heart and skeletal muscle by inactivating ribonucleotide reductase (RNR), a key enzyme for the de novo production of dNTPs, at embryonic day 13. All other tissues had normal de novo dNTP synthesis and theoretically could supply heart and skeletal muscle with deoxyribonucleosides needed for dNTP production by salvage. We observed that the dNTP and NTP pools in wild-type postnatal hearts are unexpectedly asymmetric, with unusually high dGTP and GTP levels compared with those in whole mouse embryos or murine cell cultures. We found that RNR inactivation in heart led to strongly decreased dGTP and increased dCTP, dTTP, and dATP pools; aberrant DNA replication; defective expression of muscle-specific proteins; progressive heart abnormalities; disturbance of the cardiac conduction system; and lethality between the second and fourth weeks after birth. We conclude that dNTP salvage cannot substitute for de novo dNTP synthesis in the heart and that cardiomyocytes and myocytes initiate DNA replication despite an inadequate dNTP supply. We discuss the possible reasons for the observed asymmetry in dNTP and NTP pools in wildtype hearts.

Place, publisher, year, edition, pages
2019. article id jbc.RA119.009492
Keywords [en]
cardiac function, cardiac muscle, dNTP metabolism, dNTP salvage, deoxyribonucleoside kinases, desmin, heart development, nucleoside/nucleotide biosynthesis, nucleoside/nucleotide metabolism, ribonucleotide reductase
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-161767DOI: 10.1074/jbc.RA119.009492PubMedID: 31300555OAI: oai:DiVA.org:umu-161767DiVA, id: diva2:1339513
Funder
Swedish Research CouncilSwedish Cancer SocietyAvailable from: 2019-07-30 Created: 2019-07-30 Last updated: 2019-08-06

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Tran, PhongWanrooij, Paulina H.Lorenzon, PaoloSharma, SushmaThelander, LarsNilsson, Anna KarinOlofsson, Anna-KarinMedini, Paolovon Hofsten, JonasStål, PerChabes, Andrei

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Tran, PhongWanrooij, Paulina H.Lorenzon, PaoloSharma, SushmaThelander, LarsNilsson, Anna KarinOlofsson, Anna-KarinMedini, Paolovon Hofsten, JonasStål, PerChabes, Andrei
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Department of Medical Biochemistry and BiophysicsDepartment of Integrative Medical Biology (IMB)Molecular Infection Medicine Sweden (MIMS)Umeå Centre for Molecular Medicine (UCMM)
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Journal of Biological Chemistry
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