Histidine to glutamine substitutants, a regulated process that impacts cell survival and suggests histidine shortage in cancer

Mechanistically, we propose that H>Q is a result of tRNA misalignment, and used tRNA glutamine (tRNA(Gln)) modifications at the wobble position to demonstrate it. We further show that URM1-mediated U34 thiolation boosts H>Q production and influences the survival of cancer cells following histidine deprivation, suggesting a potential role for H>Q. Additional characterization of H>Q substitutants revealed preferred sequences and the maintenance of H>Q host protein expression despite the absence of histidine, indicating cellular regulation and functional consequences.

Thus, histidine shortage induces H>Q substitutants, a regulated mistranslation event that pinpoints histidine limitation in cancer and impacts cell survival.