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bioRxiv · 10.1101/830745

Clofarabine commandeers the RNR-alpha-ZRANB3 nuclear signaling axis

Long, M. J.·Zhao, Y.·Aye, Y.
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Abstract

Ribonucleotide reductase (RNR) is an essential enzyme in DNA-biogenesis and a target of several chemotherapeutics. Here we investigate how anti-leukemic drugs [e.g., clofarabine (ClF)] that target one of the two subunits of RNR, RNR-, affect non-canonical RNR- functions. We discovered that these clinically-approved RNR-inhibiting dATP-analogs inhibit growth by also targeting ZRANB3--a newly-identified DNA-synthesis promoter and nuclear-localized interactor of RNR-. Remarkably, in early time points following drug treatment, ZRANB3-targeting accounted for most of the drug-induced DNA-synthesis suppression and multiple cell types featuring ZRANB3-knockout/knockdown were resistant to these drugs. Additionally, ZRANB3 plays a major role in regulating tumor-invasion and H-rasG12V-promoted transformation in a manner dependent on the recently-discovered interactome of RNR- involving select cytosolic-/nuclear-localized protein-players. The H-rasG12V-promoted transformation--which we show requires ZRANB3-supported DNA-synthesis--was efficiently suppressed by ClF. Such overlooked mechanisms-of-action of approved drugs and a new example of non-oncogene addiction, which is suppressed by RNR-, may advance cancer interventions.

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Long, M. J., Zhao, Y., Aye, Y.. 2019-11-04. Clofarabine commandeers the RNR-alpha-ZRANB3 nuclear signaling axis. https://doi.org/10.1101/830745

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