ASCH Domain-Containing Proteins Act as tRNA N4-acetylcytidine Erasers

N4-acetylcytidine (ac4C) is a conserved RNA modification that enhances RNA stability and translation accuracy. Emerging evidence suggests that ac4C levels can change in response to cellular and environmental triggers. Despite these indications of regulatory dynamics, the enzymes responsible for removing ac4C, beyond the recently proposed rRNA deacetylase SIRT7, remain largely unknown. Here, we examined 19 ASCH domain-containing proteins from bacteria, archaea, and humans to determine their possible activity in tRNA deacetylation. Despite differences in their sequences, structures, and nucleic-acid binding properties, all tested proteins were capable of removing ac4C from tRNA, revealing a conserved deacetylase activity across diverse species. The proteins were found to vary in nucleic acid recognition, including an archaeal specific helix-turn-helix domain that promotes strong tRNA binding. Together, these findings establish ASCH proteins as a widespread and previously unrecognized family of tRNA deacetylases, suggesting that enzymatic ac4C turnover may require complex regulation within the cells. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/708502v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@880691org.highwire.dtl.DTLVardef@674a13org.highwire.dtl.DTLVardef@1304045org.highwire.dtl.DTLVardef@cba7f6_HPS_FORMAT_FIGEXP M_FIG C_FIG