Presentation: 2025 ND EPSCoR Annual conference 

October 21, 2025, NDSU Memorial Union, Fargo, North Dakota

How to keep cells dormant? The enigmatic ERH repressor controls G0 mRNA transport.

ERH (Enhancer of Rudimentary Homolog) is an enigmatic deeply-conserved small protein (100% aminoacid identity from Xenopus frogs to mammals), frequently overexpressed in cancers, but still of unknown molecular function. We identified ERH as a novel factor becoming essential for cell viability specifically during cell dormancy and cell quiescence/G0. Using genetic, genomic and biochemical approaches, we took advantage of the strong phenotype of ERH mutants in the G0 model eukaryote S. pombe to characterize ERH molecular function in-depth. We found that ERH mediates post-transcriptional silencing of developmental transcripts and nuclear retention of specific RNAs. By developing a novel G0 reporter system tethering ERH to the reporter RNA, we showed that ERH is an effector directly inhibiting RNA export, independent of all known gene silencing pathways (such as RNA interference and H3K9 methylation). Instead, ERH intercepts the conserved RNA export adapter Mlo3/ALYREF, with human ERH displaying the same function even in yeast cells. We propose the first unified model for the seemingly diverse functions of ERH across eukaryotic evolution: (1) recruitment to specific mRNAs by diverse RNA-binding proteins; where (2) ERH inhibits mRNA export by intercepting ALYREF at the nuclear pore periphery, providing a time-window for RNA degradation or RNA processing. Our model provides a molecular basis for ERH eukaryotic conservation and reveals new avenues to target RNA metabolism in dormant cancer cells.