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

Jankevicius, Gytis; Hassler, Markus; Golia, Barbara; Rybin, Vladimir; Zacharias, Martin; Timinszky, Gyula; Ladurner, Andreas G.

doi:10.1038/nsmb.2523

Cited by 293 publications

(489 citation statements)

References 39 publications

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“…Certain PARPs, such as PARP-2, PARP-3, and PARP-7, exhibit differential localization in the nucleus and the cytoplasm during different phases of the cell cycle (Vyas et al 2013). Moreover, as mentioned in the previous section, the ADP-ribose hydrolases also exhibit distinct subcellular localizations (Niere et al 2012;Jankevicius et al 2013;Sharifi et al 2013). Taken together, these observations suggest that the compartmentalization of the "feeders," "writers," and "erasers" could be essential for rapid and coordinated changes in ADP-ribosylation in different subcellular milieus.…”

Section: Nicotinamide Mononucleotide Adenylyl Transferases (Nmnats): mentioning

confidence: 99%

“…For example, the accumulation of PAR due to loss of PARG activity causes early embryonic lethality as well as increased sensitivity to genotoxic stress (Koh et al 2004). Interestingly, the "erasers" have different subcellular localizations: MacroD1 and ARH3 localize to the mitochondria (Niere et al 2012;Jankevicius et al 2013), whereas MacroD2 and TARG localize predominantly to the nucleus Sharifi et al 2013). This suggests possible localized turnover of PAR, adding another layer of complexity to the regulation of cellular processes by ADP-ribosylation.…”

Section: Adp-ribose and Par Hydrolases: Erasersmentioning

confidence: 99%

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PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

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The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.ADP-ribosylation is a reversible post-translational modification (PTM) of proteins resulting in the covalent attachment of a single ADP-ribose unit [i.e., mono(ADP-ribose) (MAR)] or polymers of ADP-ribose units [i.e., poly(ADP-ribose) (PAR)] on a variety of amino acid residues on target proteins (Gibson and Kraus 2012;Daniels et al. 2015a). This modification is mediated by a diverse group of ADPribosyl transferase (ADPRT) enzymes that use ADP-ribose units derived from β-NAD + to catalyze the ADP-ribosylation reaction. These enzymes include bacterial ADPRTs (e.g., cholera toxin and diphtheria toxin) as well as members of three different protein families in yeast and animals: (1) arginine-specific ecto-enzymes (ARTCs), (2) sirtuins, and (3) PAR polymerases (PARPs) . Surprisingly, a recent study showed that the bacterial toxin DarTG can ADP-ribosylate DNA . How this fits into the broader picture of cellular ADP-ribosylation has yet to be determined.In this review, we focus on the mono(ADP-ribosyl)ation (MARylation) and poly(ADP-ribosyl)ation (PARylation) of glutamate, aspartate, and lysine residues by PARP family members. While many reviews have been written on PARPs in the past decade, we highlight the current trends and ideas in the field, in particular those discoveries that have been published in the past 2-3 years.

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Section: Nicotinamide Mononucleotide Adenylyl Transferases (Nmnats): mentioning

confidence: 99%

Section: Adp-ribose and Par Hydrolases: Erasersmentioning

confidence: 99%

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

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“…ing 2 (MacroD2, C20orf133), and OARD1 (TARG1, C6orf130) have recently been identified as mono-ADPribosylhydrolases [3,4]. The Macro domain (∼25 kDa) is an evolutionarily conserved domain structure acting as a binding module for metabolites of NAD + such as ADP-ribose and likely to play important roles in multiple biological processes [5,6].…”

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confidence: 99%

Biochemical and Morphological Characterization of a Neurodevelopmental Disorder-Related Mono-ADP-Ribosylhydrolase, MACRO Domain Containing 2

et al. 2018

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MACRO Domain Containing 2 (MacroD2) is a neurodevelopmental disorder-related mono-ADP-ribosylhydrolase. Molecular features of this protein in neural tissues are largely unknown. In this study, we generated a specific antibody against MacroD2, and carried out expression and morphological analyses of the molecule during mouse brain development. In Western blotting, 2 MacroD2 isoforms with molecular masses of ∼70 and ∼75 kDa started to be expressed at embryonic day 16.5, reached the maximal level at postnatal day 8, and then gradually decreased through P30. In contrast, other isoforms with molecular masses of ∼110 and ∼140 kDa gradually increased during embryonic to postnatal development. In immunohistochemical analyses, MacroD2 was strongly detected in cortical neurons in layer II–V at P0 and P7, while the protein expression decreased significantly in the neurons at P30. Immunofluorescence analyses revealed that MacroD2 was mainly distributed in the soma and to a lesser extent in the axon and dendrite of immature primary cultured mouse hippocampal neurons. On the other hand, in the matured hippocampal neurons, while MacroD2 was detected in the soma, it displayed in dendrites a punctate distribution pattern with a partial colocalization with synaptic markers, synaptophysin, and PSD95. The obtained results indicate that MacroD2 is expressed and may have a physiological role in the central nervous system during brain development.

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“…Although PARG rapidly degrades PAR, it cannot remove the proximal ADP-ribose unit from ribosylated proteins [78,81,84]. This may be achieved by the specialised macro domain-containing proteins MacroD1, MacroD2 and C6orf130/TARG1 [85][86][87]. These three proteins are recruited to sites of laserinduced DNA damage in a PARP1-dependent manner, and depletion of C6orf130 confers sensitivity to H 2 O 2 and MMS, suggesting an important role for these proteins in SSBR [87].…”

Section: Degradation Of Parmentioning

confidence: 94%

The Role of PARPs in DNA Strand Break Repair

Rulten

Dantzer

Caldecott

2015

Cancer Drug Discovery and Development

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ADP-ribosylation is a post-translational modification in which a target protein becomes modified with monomeric, short chains, or long branching chains of ADP-ribose (ADPR). The process can be carried out by a number of ADP-ribosyltransferases and polymerases (ADP-RTs and PARPs) and the consequences of ribosylation are as diverse and heterogeneous as the products that are formed. In mammalian cells, only three PARPs bind to DNA, and their activity is stimulated by DNA ends. A number of roles for these three PARPs have been characterised, including several functions in DNA repair. The known repertoire of ADPR-binding proteins is vastly expanding, meaning that ribosylation increases the rate and complexity of ways in which DNA is repaired by a number of different ways.

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

Cited by 293 publications

References 39 publications

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

Biochemical and Morphological Characterization of a Neurodevelopmental Disorder-Related Mono-ADP-Ribosylhydrolase, MACRO Domain Containing 2

The Role of PARPs in DNA Strand Break Repair

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