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A family of macrodomain proteins reverses cellular mono-ADP-ribosylation

Nat Struct Mol Biol. 2013 Mar 10. doi: 10.1038/nsmb.2523. [Epub ahead of print]

Authors/Editors: Jankevicius G, Hassler M, Golia B, Rybin V, Zacharias M, Timinszky G, Ladurner AG.
Publication Date: 2013

jankevicius-nat-struct-mol-biol-2013

Abstract

ADP-ribosylation is a reversible post-translational modification with wide-ranging biological functions in all kingdoms of life. A variety of enzymes use NAD(+) to transfer either single or multiple ADP-ribose (ADPr) moieties onto distinct amino acid substrates, often in response to DNA damage or other stresses. Poly-ADPr-glycohydrolase readily reverses poly-ADP-ribosylation induced by the DNA-damage sensor PARP1 and other enzymes, but it does not remove the most proximal ADPr linked to the target amino acid. Searches for enzymes capable of fully reversing cellular mono-ADP-ribosylation back to the unmodified state have proved elusive, which leaves a gap in the understanding of this modification. Here, we identify a family of macrodomain enzymes present in viruses, yeast and animals that reverse cellular ADP-ribosylation by acting on mono-ADP-ribosylated substrates. Our discoveries establish the complete reversibility of PARP-catalyzed cellular ADP-ribosylation as a regulatory modification.

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