| Autor: |
Fu Y; Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY, USA., Long MJC; Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY, USA., Wisitpitthaya S; Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY, USA., Inayat H; Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada., Pierpont TM; Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA., Elsaid IM; Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY, USA., Bloom JC; Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA., Ortega J; Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada., Weiss RS; Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA., Aye Y; Ecole Polytechnique Fédérale de Lausanne, Institute of Chemical Sciences and Engineering, Lausanne, Switzerland. yimon.aye@epfl.ch. |
| Abstrakt: |
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. |
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