Clofarabine Commandeers the RNR-?-ZRANB3 Nuclear Signaling Axis.

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 recently 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. In addition, ZRANB3 plays a major role in regulating tumor invasion and H-ras^G12V-promoted transformation in a manner dependent on the recently discovered interactome of RNR-? involving select cytosolic-/nuclear-localized protein players. The H-ras^G12V-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 previously unappreciated example of non-oncogene addiction, which is suppressed by RNR-?, may advance cancer interventions.

SUBMITTER: Long MJC 

PROVIDER: S-EPMC6980387 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature