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

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          Abstract

          ADP-ribosylation catalyzed by PARPs and sirtuins is an important post-translation modification. Macrodomain proteins MacroD1 and D2 are now shown to preferentially bind mono-ADP-ribosylated proteins and to act as proximal ADP-ribosylhydrolases. The crystal structure of the MacroD2–ADPr complex suggests a catalytic mechanism for the reaction.

          Supplementary information

          The online version of this article (doi:10.1038/nsmb.2523) contains supplementary material, which is available to authorized users.

          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.

          Supplementary information

          The online version of this article (doi:10.1038/nsmb.2523) contains supplementary material, which is available to authorized users.

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          Poly(ADP-ribose): novel functions for an old molecule.

          Valérie Schreiber, Françoise Dantzer, Jean-Christophe Amé … (2006)
          The addition to proteins of the negatively charged polymer of ADP-ribose (PAR), which is synthesized by PAR polymerases (PARPs) from NAD(+), is a unique post-translational modification. It regulates not only cell survival and cell-death programmes, but also an increasing number of other biological functions with which novel members of the PARP family have been associated. These functions include transcriptional regulation, telomere cohesion and mitotic spindle formation during cell division, intracellular trafficking and energy metabolism.
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            Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions.

            D D'Amours, S Desnoyers, I. D'silva … (1999)
            Poly(ADP-ribosyl)ation is a post-translational modification of proteins. During this process, molecules of ADP-ribose are added successively on to acceptor proteins to form branched polymers. This modification is transient but very extensive in vivo, as polymer chains can reach more than 200 units on protein acceptors. The existence of the poly(ADP-ribose) polymer was first reported nearly 40 years ago. Since then, the importance of poly(ADP-ribose) synthesis has been established in many cellular processes. However, a clear and unified picture of the physiological role of poly(ADP-ribosyl)ation still remains to be established. The total dependence of poly(ADP-ribose) synthesis on DNA strand breaks strongly suggests that this post-translational modification is involved in the metabolism of nucleic acids. This view is also supported by the identification of direct protein-protein interactions involving poly(ADP-ribose) polymerase (113 kDa PARP), an enzyme catalysing the formation of poly(ADP-ribose), and key effectors of DNA repair, replication and transcription reactions. The presence of PARP in these multiprotein complexes, in addition to the actual poly(ADP-ribosyl)ation of some components of these complexes, clearly supports an important role for poly(ADP-ribosyl)ation reactions in DNA transactions. Accordingly, inhibition of poly(ADP-ribose) synthesis by any of several approaches and the analysis of PARP-deficient cells has revealed that the absence of poly(ADP-ribosyl)ation strongly affects DNA metabolism, most notably DNA repair. The recent identification of new poly(ADP-ribosyl)ating enzymes with distinct (non-standard) structures in eukaryotes and archaea has revealed a novel level of complexity in the regulation of poly(ADP-ribose) metabolism.
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              Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going?

              Denise M. Elser, Sandra S Haenni, Paul Hassa … (2006)
              Since poly-ADP ribose was discovered over 40 years ago, there has been significant progress in research into the biology of mono- and poly-ADP-ribosylation reactions. During the last decade, it became clear that ADP-ribosylation reactions play important roles in a wide range of physiological and pathophysiological processes, including inter- and intracellular signaling, transcriptional regulation, DNA repair pathways and maintenance of genomic stability, telomere dynamics, cell differentiation and proliferation, and necrosis and apoptosis. ADP-ribosylation reactions are phylogenetically ancient and can be classified into four major groups: mono-ADP-ribosylation, poly-ADP-ribosylation, ADP-ribose cyclization, and formation of O-acetyl-ADP-ribose. In the human genome, more than 30 different genes coding for enzymes associated with distinct ADP-ribosylation activities have been identified. This review highlights the recent advances in the rapidly growing field of nuclear mono-ADP-ribosylation and poly-ADP-ribosylation reactions and the distinct ADP-ribosylating enzyme families involved in these processes, including the proposed family of novel poly-ADP-ribose polymerase-like mono-ADP-ribose transferases and the potential mono-ADP-ribosylation activities of the sirtuin family of NAD(+)-dependent histone deacetylases. A special focus is placed on the known roles of distinct mono- and poly-ADP-ribosylation reactions in physiological processes, such as mitosis, cellular differentiation and proliferation, telomere dynamics, and aging, as well as "programmed necrosis" (i.e., high-mobility-group protein B1 release) and apoptosis (i.e., apoptosis-inducing factor shuttling). The proposed molecular mechanisms involved in these processes, such as signaling, chromatin modification (i.e., "histone code"), and remodeling of chromatin structure (i.e., DNA damage response, transcriptional regulation, and insulator function), are described. A potential cross talk between nuclear ADP-ribosylation processes and other NAD(+)-dependent pathways is discussed.
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                Author and article information

                Contributors
                Gyula Timinszky: gyula.timinszky@med.uni-muenchen.de
                Andreas G Ladurner: andreas.ladurner@med.uni-muenchen.de
                Journal
                Journal ID (nlm-ta): Nat Struct Mol Biol
                Journal ID (iso-abbrev): Nat. Struct. Mol. Biol
                Title: Nature Structural & Molecular Biology
                Publisher: Nature Publishing Group US (New York )
                ISSN (Print): 1545-9993
                ISSN (Electronic): 1545-9985
                Publication date (Electronic): 10 March 2013
                Publication date (Print): 2013
                Volume: 20
                Issue: 4
                Pages: 508-514
                Affiliations
                [1 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Butenandt Institute of Physiological Chemistry, Ludwig Maximilians University of Munich, ; Munich, Germany
                [2 ]International Max Planck Research School for Molecular and Cellular Life Sciences, Martinsried, Germany
                [3 ]GRID grid.4709.a, ISNI 0000 0004 0495 846X, European Molecular Biology Laboratory, ; Heidelberg, Germany
                [4 ]GRID grid.6936.a, ISNI 0000000123222966, Department of Physics, , Biomolecular Dynamics Unit, Technical University of Munich, ; Garching, Germany
                [5 ]GRID grid.452329.b, Center for Integrated Protein Science Munich, ; Munich, Germany
                [6 ]GRID grid.452617.3, Munich Cluster for Systems Neurology, ; Munich, Germany
                Article
                Publisher ID: BFnsmb2523
                DOI: 10.1038/nsmb.2523
                PMC ID: 7097781
                PubMed ID: 23474712
                SO-VID: f757473e-b1b1-4e7c-8c37-e6ef7354a454
                Copyright © © Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2013
                License:

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Date received : 6 September 2012
                Date accepted : 22 January 2013
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s), under exclusive licence to Springer Nature America, Inc. 2013

                ScienceOpen disciplines: Molecular biology
                Keywords: hydrolases,post-translational modifications,structural biology
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: hydrolases, post-translational modifications, structural biology

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