Identification of Macrodomain Proteins as Novel O-Acetyl-ADP-ribose Deacetylases
Abstract
Sirtuins are a family of protein lysine deacetylases, which regulate gene silencing, metabolism, life span, and chromatin structure. Sirtuins utilize NAD(+) to deacetylate proteins, yielding O-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 reaction OAADPr is a substrate for several related macrodomain proteins: human MacroD1, human MacroD2, Escherichia coli YmdB, and the sirtuin-linked MacroD-like protein from Staphylococcus 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 as OAADPr deacetylases and potential in vivo regulators of cellular OAADPr produced by NAD(+)-dependent deacetylation.
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BibTeX
@article{chen2026identification,
title = {{Identification of Macrodomain Proteins as Novel O-Acetyl-ADP-ribose Deacetylases}},
author = {Dawei Chen and Melanie Vollmar and Marianna Rossi and Claire Phillips and Rolf Kraehenbuehl and Dea Slade and Pawan Mehrotra and Frank von Delft and Susan Crosthwaite and Opher Gileadi and John Denu and Ivan Ahel},
journal = {Journal of Biological Chemistry},
year = {2026},
month = oct,
doi = {10.1074/jbc.m110.206771},
url = {https://hal.science/hal-05787729v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Identification of Macrodomain Proteins as Novel O-Acetyl-ADP-ribose Deacetylases
AU - Dawei Chen
AU - Melanie Vollmar
AU - Marianna Rossi
AU - Claire Phillips
AU - Rolf Kraehenbuehl
AU - Dea Slade
AU - Pawan Mehrotra
AU - Frank von Delft
AU - Susan Crosthwaite
AU - Opher Gileadi
AU - John Denu
AU - Ivan Ahel
PY - 2026
DA - 2026/10/08
JO - Journal of Biological Chemistry
DO - 10.1074/jbc.m110.206771
UR - https://hal.science/hal-05787729v1
AB - Sirtuins are a family of protein lysine deacetylases, which regulate gene silencing, metabolism, life span, and chromatin structure. Sirtuins utilize NAD(+) to deacetylate proteins, yielding O-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 reaction OAADPr is a substrate for several related macrodomain proteins: human MacroD1, human MacroD2, Escherichia coli YmdB, and the sirtuin-linked MacroD-like protein from Staphylococcus 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 as OAADPr deacetylases and potential in vivo regulators of cellular OAADPr produced by NAD(+)-dependent deacetylation.
SN - 0021-9258
SN - 1083-351X
ER -