Nuclear RNR-α antagonizes cell proliferation by directly inhibiting ZRANB3

Since the origins of DNA-based life, the enzyme ribonucleotide reductase (RNR) has spurred proliferation because of its rate-limiting role in de novo deoxynucleoside-triphosphate (dNTP) biosynthesis. Paradoxically, the large subunit, RNR-α, of this obligatory two-component complex in mammals plays a...

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Published in:	Nature chemical biology Vol. 14; no. 10; pp. 943 - 954
Main Authors:	Fu, Yuan, Long, Marcus J. C., Wisitpitthaya, Somsinee, Inayat, Huma, Pierpont, Timothy M., Elsaid, Islam M., Bloom, Jordana C., Ortega, Joaquin, Weiss, Robert S., Aye, Yimon
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-10-2018 Nature Publishing Group
Subjects:	631/337/1644 631/67 631/80/86 631/92/613 Active Transport, Cell Nucleus Animals Biochemical Engineering Biochemistry Biological activity Bioorganic Chemistry Biosynthesis Cell Biology Cell Cycle Cell Nucleus - metabolism Cell Proliferation Cercopithecus aethiops Chemistry Chemistry and Materials Science Chemistry/Food Science COS Cells Cytosol - metabolism Deoxyribonucleic acid DNA DNA - analysis DNA biosynthesis DNA Damage DNA Helicases - antagonists & inhibitors DNA Replication Fibroblasts - metabolism Growth rate HEK293 Cells HeLa Cells Humans K562 Cells Mice Mutagenesis Mutation NIH 3T3 Cells Nuclear transport Nucleotides Protein Binding Reductase Reductases Ribonucleotide reductase Ribonucleotide Reductases - metabolism RNA, Small Interfering - metabolism Signal Transduction
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Summary:	Since the origins of DNA-based life, the enzyme ribonucleotide reductase (RNR) has spurred proliferation because of its rate-limiting role in de novo deoxynucleoside-triphosphate (dNTP) biosynthesis. Paradoxically, the large subunit, RNR-α, of this obligatory two-component complex in mammals plays a context-specific antiproliferative role. There is little explanation for this dichotomy. Here, we show that RNR-α has a previously unrecognized DNA-replication inhibition function, leading to growth retardation. This underappreciated biological activity functions in the nucleus, where RNR-α interacts with ZRANB3. This process suppresses ZRANB3’s function in unstressed cells, which we show to promote DNA synthesis. This nonreductase function of RNR-α is promoted by RNR-α hexamerization—induced by a natural and synthetic nucleotide of dA/ClF/CLA/FLU—which elicits rapid RNR-α nuclear import. The newly discovered nuclear signaling axis is a primary defense against elevated or imbalanced dNTP pools that can exert mutagenic effects irrespective of the cell cycle. The large subunit of ribonucleotide reductase RNR-α downregulates DNA replication in the nucleus by directly disrupting PCNA and ZRANB3 interactions. RNR-α nuclear entry is regulated by an interplay between IRBIT and importin-α1.
Bibliography:	AUTHOR CONTRIBUTIONS Y.F., M.J.C.L. and Y.A. designed the experiments. Y.F. and M.J.C.L. performed the experiments. S.W. synthesized ClF-, ClA- and FlU-nucleotides. H.I. and J.O. performed electron microscopy analysis. I.M.E. assisted M.J.C.L. with targeted mutagenesis for binding site analysis. M.J.C.L., T.M.P., J.C.B. and R.S.W. generated mouse embryonic fibroblast cultures. Y. F., M.J.C.L. and Y.A. analyzed and interpreted the data. Y.F., M.J.C.L. and Y. A. wrote the paper with proof-editing contributions from R.S.W. and J.O.
ISSN:	1552-4450 1552-4469
DOI:	10.1038/s41589-018-0113-5