Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases.

Sirtuins are a family of protein lysine deacetylases, which regulate gene silencing, metabolism, life span, and chromatin structure. Sirtuins utilize NAD+ to deacetylate proteins, yieldingO-acetyl-ADP-ribose (OAADPr) as a reaction product. The macrodomain is a ubiquitous protein module known to bind ADP-ribose derivatives, which diverged through evolution to support many different protein functions and pathways. The observation that some sirtuins and macrodomains are physically linked as fusion proteins or genetically coupled through the same operon, provided a clue that their functions might be connected. Indeed, here we demonstrate that the product of the sirtuin reactionOAADPr is a substrate for several related macrodomain proteins: human MacroD1, human MacroD2,Escherichia coliYmdB, and the sirtuin-linked MacroD-like protein fromStaphylococcus aureus. In addition, we show that the cell extracts derived from MacroD-deficient Neurospora crassa strain exhibit a major reduction in the ability to hydrolyze OAADPr. Our data support a novel function of macrodomains asOAADPr deacetylases and potentialin vivoregulators of cellularOAADPr produced by NAD+ -dependent deacetylation