ADP-ribosylation from molecular mechanisms to therapeutic implications

Suskiewicz, Marcin J.; Prokhorova, Evgeniia; Rack, Johannes G.M.; Ahel, Ivan

doi:10.1016/j.cell.2023.08.030

Cited by 38 publications

(18 citation statements)

References 190 publications

(326 reference statements)

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“…283 On the other hand, using site-specifically modified proteins as substrates, the specificity of demodifying enzymes such as phosphatases and deacetylases can be precisely determined. Besides PTMs discussed in this review, some other PTMs such as ADP-ribosylation, 384 neddylation (NEDD8, a Ub-like protein), 385 and S-nitrosylation 386 have also been found in nature. Further developing OTSs for them or their analogs will enlarge the existing library of PTM-OTSs, providing sufficient tools for studies on emerging PTMs.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

Gan,

Fan

2024

Chem. Rev.

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Post-translational modifications (PTMs) endow proteins with new properties to respond to environmental changes or growth needs. With the development of advanced proteomics techniques, hundreds of distinct types of PTMs have been observed in a wide range of proteins from bacteria, archaea, and eukarya. To identify the roles of these PTMs, scientists have applied various approaches. However, high dynamics, low stoichiometry, and crosstalk between PTMs make it almost impossible to obtain homogeneously modified proteins for characterization of the site-specific effect of individual PTM on target proteins. To solve this problem, the genetic code expansion (GCE) strategy has been introduced into the field of PTM studies. Instead of modifying proteins after translation, GCE incorporates modified amino acids into proteins during translation, thus generating site-specifically modified proteins at target positions. In this review, we summarize the development of GCE systems for orthogonal translation for site-specific installation of PTMs.

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Section: Summary and Perspectivesmentioning

confidence: 99%

Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

Gan,

Fan

2024

Chem. Rev.

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“…Our work reveals the first case, to our knowledge, of an ADP-ribosyltransferase that specifically targets mRNA. Prior studies have identified numerous ADP-ribosyltransferases in phages, bacteria, and eukaryotes that use the highly abundant and reactive molecule NAD + to covalently modify a wide range of proteins, often to reversibly regulate their activities [1][2][3] . Protein ADP-ribosyltransferases are also featured in many biological conflicts with secreted toxins such as pertussis and cholix toxins capable of shutting down key cellular processes by modifying specific target proteins 5,35 .…”

Section: Adp-ribosylation Of Mrnamentioning

confidence: 99%

“…ADP-ribosyltransferases are important enzymes found throughout biology [1][2][3] . These enzymes transfer the ADP-ribose moiety of NAD + onto other biomolecules, usually modifying an amino acid on a target protein.…”

Section: Introductionmentioning

confidence: 99%

Anti-viral defense by an ADP-ribosyltransferase that targets mRNA to block translation

Vassallo,

Doering,

Laub

2024

Preprint

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Host-pathogen conflicts are crucibles of molecular innovation. Selection for immunity to pathogens has driven the evolution of sophisticated immunity mechanisms throughout biology, including in bacteria that must evade their viral predators known as bacteriophages. Here, we characterize a widely distributed anti-phage defense system, CmdTAC, that provides robust defense against infection by the T-even family of phages. Our results support a model in which CmdC detects infection by sensing viral capsid proteins, ultimately leading to the activation of a toxic ADP-ribosyltransferase effector protein, CmdT. We show that newly synthesized capsid protein triggers dissociation of the chaperone CmdC from the CmdTAC complex, leading to destabilization and degradation of the antitoxin CmdA, with consequent liberation of the CmdT ADP-ribosyltransferase. Strikingly, CmdT does not target a protein, DNA, or structured RNA, the known targets of other ADP-ribosyltransferases. Instead, CmdT modifies the N6 position of adenine in GA dinucleotides within single-stranded RNAs leading to arrest of mRNA translation and the inhibition of viral replication. Our work reveals a new mechanism of anti-viral defense and a previously unknown but broadly distributed class of ADP-ribosyltransferases that target mRNA.

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“…Proteins of the poly(ADP-ribosyl) polymerase -short PARP -family are defined by a common, structurally highly conserved catalytic ADP-ribosyltransferase (ART) domain [1]. ADPribosylation, in which the ADP-ribose moiety from NAD+ is transferred onto target molecules, partakes in the regulation of processes including DNA damage repair, transcription and translation, protein homeostasis, and antiviral defense [2][3][4]. ADP-ribosylation is of prime therapeutic interest due to its contribution to DNA damage repair and de-regulated signaling pathways in cancers [5,6].…”

Section: Introductionmentioning

confidence: 99%

Regulation of ADP-ribosyltransferase activity by ART domain dimerization in PARP15

Ebenwaldner,

García Saura,

Ekström

et al. 2024

Preprint

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PARP15 is a mono-ADP-ribosyltransferase with unknown functions. Its evolutionary relationship with PARP14 suggests roles in antiviral defense; its ability to modify RNA and localization to stress granules point to functions in the regulation of translation. As many other PARP family members, PARP15 will readily automodify in vitro. PARP15 also contains two macrodomains predicted to bind ADP-ribosyl on targets. We used biochemical and biophysical analysis to study how the ADP-ribosyltransferase activity of PARP15 is regulated. Here we show that the catalytic domain of PARP15 dimerizes with mid-nanomolar affinity, forming the same dimer interface in solution that had already been captured by X-ray crystallography of the domain. Furthermore, we show that the formation of dimers is a prerequisite for catalytic activity and that monomeric mutant variants of the domain were catalytically inactive. Our findings suggest a regulatory mechanism by which dimerization activates either target engagement or placement of a catalytic residue, rather than NAD+ co-substrate binding, and by which the two protomers of the dimer operate independent of one another. Together, our results uncover a novel mechanism of regulation in a PARP family enzyme, which might inspire new avenues of pharmacological intervention.

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ADP-ribosylation from molecular mechanisms to therapeutic implications

Cited by 38 publications

References 190 publications

Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

Anti-viral defense by an ADP-ribosyltransferase that targets mRNA to block translation

Regulation of ADP-ribosyltransferase activity by ART domain dimerization in PARP15

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