College of Veterinary Medicine
This group has identified a new paradigm for eukaryotic translation control for cap-dependent translation of select mRNAs during aging, cancer and physiological cell stress. Activation of mammalian target of rapamycin (mTOR) is necessary for eukaryotic translation initiation factor 4E (eIF4E)-dependent translation. The noncanonical cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 3 and adaptor NCBP1 was identified and proposed to support mTOR-resistant mRNA translation. These researchers have presented evidence that unique JunD polysomes selectively engage NCBP1, NCBP3 and RNA helicase A (DHX9/RHA) in messenger ribonucleoprotein complexes (mRNPs) necessary for mTOR resistant translation.
DHX9/RHA binds JunD mRNA through two conserved double-stranded RNA binding domains and tethers the NCBP1/NCBP3 mRNP to polysomes. Importantly, JunD polysomes are retained during mTOR inhibition of eIF4E-dependent translation until DHX9/RHA is downregulated by siRNA. The evidence documents DHX9/RHA is necessary for mTOR-resistant translation of the JunD tumor suppressor protein, and by extension, the small cadet of mTOR resistant genes that we continue to characterize.
DHX9/RHA binds selected mRNAs within a structured 5′ terminal PCE and facilitates polyribosome association. A principle gap in knowledge is how RHA engages an RNP complex that facilitates translation activity versus circular RNA that facilitates regulates innate sensing by RHA and other canonical double stranded RNA binding proteins, e.g. RIGi.