Nuclear RNR-α antagonizes cell proliferation by directly inhibiting ZRANB3.
Nuclear RNR-α antagonizes cell proliferation by directly inhibiting ZRANB3.
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DOI：
10.1038/s41589-018-0113-5
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发表时间：
2018-10
影响因子：
14.8
通讯作者：
Aye Y
中科院分区：
文献类型：
--
作者：
Fu Y;Long MJC;Wisitpitthaya S;Inayat H;Pierpont TM;Elsaid IM;Bloom JC;Ortega J;Weiss RS;Aye Y
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 anti-proliferative role. There is little explanation for this dichotomy. Here, we show that RNR-αhas 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 that we show to be promotion of DNA-synthesis. This non-reductase-function of RNR-α is promoted by RNR-α-hexamerization—induced by 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/imbalanced dNTP-pools that can exert mutagenic effects irrespective of the cell cycle. Double Agent Exposed! The large subunit of ribonucleotide reductase—the harbinger of the DNA world—downregulates replication when inside the nucleus: it plays a tug-of-war with IRBIT/importin-α1 in the cytosol and PCNA/ZRANB3 in the nucleus.
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影响因子：
64.5
作者：
Davoli T;Xu AW;Mengwasser KE;Sack LM;Yoon JC;Park PJ;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
3.7
作者：
FONG, KM;ZIMMERMAN, PV;SMITH, PJ
通讯作者：
SMITH, PJ
DOI：
10.1073/pnas.1013274108
发表时间：
2011-06-14
影响因子：
11.1
作者：
Aye, Yimon;Stubbe, JoAnne
通讯作者：
Stubbe, JoAnne
DOI：
10.1073/pnas.94.24.13181
发表时间：
1997-11-25
影响因子：
11.1
作者：
Fan, HZ;Huang, AP;Wright, JA
通讯作者：
Wright, JA
影响因子：
56.9
作者：
ALI, IU;LIDEREAU, R;CALLAHAN, R
通讯作者：
CALLAHAN, R