Every cell packs metres of DNA around histone proteins, and errors in modifying those histones can contribute to diseases including cancer. Researchers in the laboratory of Nenad Ban at ETH Zurich, with doctoral student Denis Yudin as first author and collaborators at the University of Konstanz and Caltech, have discovered that a molecular complex called NAC choreographs histone modification at the very moment the proteins are made. The work appears in Science Advances.
NAC, discovered about 30 years ago, sits where new protein chains emerge from the ribosome, with a ball-shaped core and four flexible extensions. The study shows it recruits two enzymes to the ribosome in strict sequence for the histones H4 and H2A: the first removes the protein's starting amino acid, the second attaches an acetyl group to the newly exposed end. Because histone chains are short and assemble quickly, both steps must happen almost instantly and in the right order.
The structural analysis reveals how one of NAC's flexible arms binds the enzyme NatD, which is often overproduced in certain cancers. Understanding how NatD gains access to the ribosome suggests therapeutic angles, such as drugs that block its binding surface or its recruitment. More broadly, the work recasts NAC as a selective gatekeeper of protein biosynthesis rather than a passive bystander at the ribosome's exit.