Fig. 1. Canonical and moonlighting functions of Dicer, Fus, and RNR-α/ZRANB3. (A) Dicer's canonical function is to trim double-stranded pre-microRNA, to form mature microRNA in the cytosol (left panel). Dicer's moonlighting role occurs in the nucleus (right panel), where Dicer processes double-stranded RNA, formed from damaged DNA, as part of the DNA Damage Response (DDR).^12,13 (B) Fus splices pre-mRNA in the nucleus to facilitate the maturation of mRNA (left panel). During moonlighting (right panel), Fus exports nuclear mRNA into the cytosol, and itself exits the nucleus passively. mRNA so exported may undergo locale-specific translation. Retrotranslocation/nuclear import of Fus by Transportin1 (TNPO1) clears cytosol-accumulated Fus. This nuclear translocation pathway is inactivated by hyperosmolarity¹⁴ in a cell-type dependent manner consistent with pathology of FTD. (C) Canonically, minimally-reductase-active quaternary state of RNR-enzyme necessitates RNR-α forming a heterotetramer with RNR-β (α₂β₂). The resulting complex catalyzes the reduction of NDPs (N = A, U, G, and C) to dNDPs. This pathway is the sole means to generate dNTPs de novo in mammalian cells, although there are salvage pathways. ZRANB3's canonical role is in DDR, whereby polyubiquitylated-PCNA recruits ZRANB3 to damage sites, allowing stressed cells to bypass/manage stalled replication forks¹⁷ (left panel). Binding of triphosphates of adenosine, and adenosine-analog drugs to RNR-α results in the formation of hexameric states (RNR-α₆), which are involved in moonlighting (right panel). (RNR-α)₆ is ushered into the nucleus by importin-α1. This process is suppressed by the (RNR-α)₆-specific-binding cytosolic protein, IRBIT. Nuclear RNR-α (irrespective of its quaternary state) directly interacts with ZRANB3, preventing the ubiquitin-independent binding of ZRANB3 to PCNA, and ultimately suppressing DNA-synthesis.^15,16 This ubiquitin-independent ZRANB3–PCNA interaction was recently discovered to promote DNA synthesis.¹⁵.