Although most of the papers in the Journal Club series describe relatively old, classic studies that inaugurated a field of research, I choose to discuss a 2017 article that illuminated my understanding of an unexpected discovery in our lab. In 2016 we found that the accumulation of nucleus-synthesized ATP in cells is required for extensive chromatin remodelling in response to external signals. In the chosen paper, the group of Anthony Hyman (MPI, Dresden) describe their attempts to understand why the concentration of ATP in cells is in the millimolar range, although the enzymes that use ATP have affinities in the nanomolar or micromolar range.

Based on the amphipathic nature of the ATP molecule, Patel et al. considered the possibility that ATP could serve as a hydrotrope that helps to maintain in solution macromolecules that otherwise would aggregate. With a series of convincing experiments, they proved this concept in the test tube and in cells, and found that the function of ATP as a hydrotrope requires millimolar concentrations and is essential for cell homeostasis. Furthermore, failure of ATP function as a hydrotrope may explain the development of degenerative diseases and ageing.

This revolutionary view of a famous molecule, long considered a carrier of energy and a co-substrate for protein phosphorylation opens completely new avenues in the emerging research of biological phase transitions. We immediately realized that only a minor fraction of the ATP made in the nucleus serves as substrate for the ATPases of the chromatin-remodelling enzymes, while the major fraction of ATP in the nucleus contributes to solubilizing chromatin and nuclear macromolecules as a hydrotrope and as a chelator of free Mg2+ ions.

the major fraction of ATP in the nucleus contributes to solubilizing chromatin and nuclear macromolecules

This insight has radically changed our approach to most of the biological processes we study, including DNA damage repair, development and cancer biology.