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A Novel Reductase‐Independent Role of Nuclear Ribonucleotide Reductase
Author(s) -
Aye Yimon
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.753.1
Subject(s) - ribonucleotide reductase , dna replication , biology , nuclear transport , context (archaeology) , nuclear protein , protein subunit , microbiology and biotechnology , dna , biochemistry , cell nucleus , nucleus , gene , transcription factor , paleontology
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. Unsurprisingly RNR is overexpressed in cancer cells, rendering RNR a major chemotherapeutic target. Paradoxically, the large subunit, RNR‐a, of this obligatory two‐component complex plays a stage‐/context‐specific tumor‐suppressive role. Little explanation has been offered to resolve this dichotomy. Here, we show that nuclear RNR‐a has an unappreciated DNA‐replication‐inhibition function, leading to growth retardation and ultimately suppression of focus formation. A large‐scale protein‐interaction study uncovered that nuclear RNR‐α is an inhibitor of a novel nuclear protein which we identify as a promoter of DNA‐synthesis. This non‐reductase‐role of RNR‐α is regulated by exclusion from the nucleus, and promoted by nucleotide‐induced RNR‐a‐oligomerization that elicits rapid nuclear import. The newly‐discovered nuclear signaling axis acts as a primary defense against elevated/imbalanced dNTP‐pools that can exert mutagenic effects irrespective of the cell cycle. (Fu and Long et al ‐ Under Peer Review‐2016 Nat Commun ). Support or Funding Information Cornell University and Weill Medicine seed grants and Cornell University start‐up funds (for Nucleotide Signaling research program in the Aye lab), and NSF CAREER, NIH Director's New Innovator, Beckman Young Investigator, and Sloan Fellowship programs (for Redox Signaling research program in the Aye lab).