DELTEX E3 ligases ubiquitylate ADP-ribosyl modification on protein substrates

Science Advances, Journal Year: 2022, Volume and Issue: 8(40)

Published: Oct. 5, 2022

Ubiquitylation had been considered limited to protein lysine residues, but other substrates have recently emerged. Here, we show that DELTEX E3 ligases specifically target the 3′ hydroxyl of adenosine diphosphate (ADP)–ribosyl moiety can be linked a protein, thus generating hybrid ADP-ribosyl-ubiquitin modification. Unlike known hydroxyl-specific E3s, which proceed via covalent E3~ubiqutin intermediate, enzymes are RING E3s stimulate direct ubiquitin transfer from E2~ubiquitin onto substrate. However, DELTEXes follow previously unidentified paradigm for whereby ligase not only forms scaffold also provides catalytic residues activate acceptor. Comparative analysis hydroxyl-ubiquitylating active sites points recurring use histidine residue, which, in is potentiated by glutamate triad-like manner. In addition, determined hydrolase specificity profile this modification, identifying human and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could reverse it cells.

Language: Английский

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Updated protein domain annotation of the PARP protein family sheds new light on biological function

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(15), P. 8217 - 8236

Published: June 3, 2023

AlphaFold2 and related computational tools have greatly aided studies of structural biology through their ability to accurately predict protein structures. In the present work, we explored AF2 models 17 canonical members human PARP family supplemented this analysis with new experiments an overview recent published data. proteins are typically involved in modification nucleic acids mono or poly(ADP-ribosyl)ation, but function can be modulated by presence various auxiliary domains. Our provides a comprehensive view structured domains long intrinsically disordered regions within PARPs, offering revised basis for understanding these proteins. Among other functional insights, study model PARP1 domain dynamics DNA-free DNA-bound states enhances connection between ADP-ribosylation RNA ubiquitin-like modifications predicting putative RNA-binding E2-related RWD certain PARPs. line bioinformatic analysis, demonstrate first time PARP14's capability activity vitro. While our insights align existing experimental data probably accurate, they need further validation experiments.

Language: Английский

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PARPs and ADP-ribosylation: Deciphering the complexity with molecular tools

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(10), P. 1552 - 1572

Published: April 28, 2023

Language: Английский

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ADP-ribose contributions to genome stability and PARP enzyme trapping on sites of DNA damage; paradigm shifts for a coming-of-age modification

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(12), P. 105397 - 105397

Published: Oct. 28, 2023

ADP-ribose is a versatile modification that plays critical role in diverse cellular processes. The addition of this catalyzed by ADP-ribosyltransferases, among which notable poly(ADP-ribose) polymerase (PARP) enzymes are intimately involved the maintenance genome integrity. modifications during DNA damage repair significant interest for proper development PARP inhibitors targeted toward treatment diseases caused genomic instability. More specifically, promoting persistence on lesions, termed "trapping," considered desirable characteristic. In review, we discuss key classes proteins signaling (writers, readers, and erasers) with focus those An overview factors modulate PARP1 PARP2 at sites lesions also discussed. Finally, clarify aspects trapping model light recent studies characterize kinetics recruitment lesions. These findings suggest could be as continuous molecules to rather than physical stalling molecules. Recent novel research tools have elevated level understanding ADP-ribosylation, marking coming-of-age interesting modification. carries necessary information many processes within cell maintaining its stability importance ensure viability. Genome instability can arise from endogenous causes, such normal transactions (replication, transcription, recombination), but exogenous like external damaging agents (1Chatterjee N. Walker G.C. Mechanisms damage, repair, mutagenesis.Environ. Mol. Mutagen. 2017; 58: 235-263Crossref PubMed Scopus (957) Google Scholar). sheer number each human experiences daily (approximately 70,000 lesions) (2Lindahl T. Barnes D.E. Repair damage.Cold Spring Harb. Symp. Quant. Biol. 2000; 65: 127-133Crossref Scholar) highlights heavy demand put mechanisms. As such, variety pathways exist tackle diversity abundance these carrying overlapping functions rely interplay between posttranslational (PTMs) (phosphorylation, ubiquitylation, SUMOylation, etc) proceed success (3Huen M.S. Chen J. response pathways: crossroad protein modifications.Cell Res. 2008; 18: 8-16Crossref (162) an ancient nucleic acid has been utilized organisms, often defense mechanism (4Lüscher B. Bütepage M. Eckei L. Krieg S. Verheugd P. Shilton B.H. multifaceted control physiology health disease.Chem. Rev. 2018; 118: 1092-1136Crossref (154) Mammalian cells employ contexts, including antiviral defense/innate immunity, homeostasis, gene regulation, repair/genome (5Luscher Ahel I. Altmeyer Ashworth A. Bai Chang et al.ADP-ribosyltransferases, update function nomenclature.FEBS 2021; 289: 7399-7410Crossref (104) Notably, single (ADPr) unit modifications, multiple ADPr joined polymer known or PAR. PAR chains linearly elongated through formation (2′-1″) ribose–ribose glycosidic bond units. Occasionally, (2″-1″) occur branches (Fig. 1A) (6Chen Q. Kassab M.A. Dantzer F. Yu X. mediates branched poly ADP-ribosylation damage.Nat. Commun. 9: 3233Crossref (97) Scholar, 7Alemasova E.E. Lavrik O.I. Poly(ADP-ribosyl)ation PARP1: reaction regulatory proteins.Nucleic Acids 2019; 47: 3811-3827Crossref (232) Although majority published investigated proteins, there growing evidence appreciation prevalence acids (8Musheev M.U. Schomacher Basu Han D. Krebs Scholz C. al.Mammalian N1-adenosine PARylation reversible modification.Nat. 2022; 13: 6138Crossref (9) 9Schuller Beyond modification: rise non-canonical ADP-ribosylation.Biochem. 479: 463-477Crossref (16) 10Weixler Scharinger K. Momoh Luscher Feijs K.L.H. Zaja R. RNA DNA: vitro characterization vivo function.Nucleic 49: 3634-3650Crossref (40) This review our current employed catalysis, turnover, signaling, enzymes. (PARPi) important biology several PARPi approved use cancer treatments. covers knowledge mode action, particular clarifying enigmatic process "trapping." ADP-ribosyltransferase (ART) take group NAD+ attach it macromolecules. Proteins modified amino sidechains, Glu, Asp, Ser, Arg, Cys Nucleic receive phosphorylated termini nucleobases diphtheria toxin-like family, containing mammalian enzymes, defined H-Y-[E/D/Q] signature motif their binding 1B). active site composed "donor" split into nicotinamide pocket, catalytic triad located, adenine pocket (7Alemasova effectively holds moiety will attached either target protein/nucleic chain undergoing elongation. elongation requires presence "acceptor" moiety, already target, new added most members family do not catalyze PARylation, they possess sites. include PARP1, PARP2, TNKS1 (PARP5a), TNKS2 (PARP5b) 1C). PARP3 participates catalyzes ADPr, mono-ADP-ribosylation (MARylation). A later section some mechanisms regulating writers specific roles maintenance. readers comprised modules recognize MAR without removing Many recruited via Among high-affinity PAR-binding (11Gagné J.P. Isabelle Lo K.S. Bourassa Hendzel M.J. Dawson V.L. al.Proteome-wide identification poly(ADP-ribose)-associated complexes.Nucleic 36: 6959-6976Crossref (320) zinc fingers (PBZs) (12Ahel Matsusaka Clark A.J. Pines Boulton S.J. al.Poly(ADP-ribose)-binding finger motifs repair/checkpoint proteins.Nature. 451: 81-85Crossref (332) For example, while p53 (a transcription activator) XPA scaffolding nucleotide excision repair) bind conserved (13Reber J.M. Mangerich Why structure length matter: biological significance underlying structural heterogeneity poly(ADP-ribose).Nucleic 8432-8448Crossref (0) Scholar), histone chaperone aprataxin polynucleotide kinase factor (APLF) two PBZ tandem APLF were found branching although currently unclear how may coordinate mediate (14Eustermann Brockmann Mehrotra P.V. Yang J.C. Loakes West S.C. al.Solution structures domains interaction poly(ADP-ribose).Nat. Struct. 2010; 17: 241-243Crossref (83) fact, preference reproduced study (15Löffler Krüger Zirak Winterhalder Müller A.L. Fischbach al.Influence poly(ADP-ribose)-protein interactions.Nucleic 2023; 51: 536-552Crossref (2) generally accepted low abundance, explain difficulty identifying specifically recognizing Other WWE BRCT 1D) Of note, RNA- DNA-recognition motifs, oligonucleotide/oligosaccharide-binding fold, interact essentially chemically similar DNA. shift PAR, RNA, DNA, depending (DDR) further discussed below. Enzymes digest remove referred erasers. Notable erasers glycohydrolase (PARG) (ADP-ribosyl)hydrolase 3 (ARH3) 1E). thorough reviews recently written about PARG, ARH3 structure, substrate recognition, (16Rack J.G.M. Liu Zorzini V. Voorneveld Ariza Honarmand Ebrahimi al.Mechanistic insights three steps poly(ADP-ribosylation) reversal.Nat. 12: 4581Crossref (33) 17Schützenhofer Rack making breaking serine-ADP-ribosylation response.Front. Cell Dev. 9745922Crossref (8) We provide summary activities section. PARG hydrolyzes high efficacy bonds chains. degrades linear chains, cannot last, protein-linked thus leaving MARylation mark targets (18Hatakeyama Nemoto Y. Ueda Hayaishi O. Purification glycohydrolase. Different modes action large small poly(ADP-ribose).J. Chem. 1986; 261: 14902-14911Abstract Full Text PDF 19Braun S.A. Panzeter P.L. Collinge Althaus F.R. Endoglycosidic cleavage polymers glycohydrolase.Eur. Biochem. 1994; 220: 369-375Crossref 20Barkauskaite E. Brassington Tan E.S. Warwicker Dunstan Banos al.Visualization bound reveals inherent balance exo- endo-glycohydrolase activities.Nat. 2013; 4: 2164Crossref (109) Interestingly, acts both exo-glycohydrolase (degrading starting terminus, releasing units) (21Slade Barkauskaite Weston Lafite Dixon al.The glycohydrolase.Nature. 2011; 477: 616-620Crossref (275) weak releases fragments (longer subsequently degraded itself, albeit inefficiently (20Barkauskaite 22Pourfarjam Kasson Tran Ho Lim Kim I.K. robust activity protein-free chains.Biochem. Biophys. 2020; 527: 818-823Crossref (13) removal left mono-ADP-ribosyl-acceptor hydrolases. one hydrolase acting DDR removes serine-linked forms (23Fontana Bonfiglio J.J. Palazzo Bartlett Matic Serine reversal ARH3.Elife. 6e28533Crossref (149) Erasers capable Glu/Asp residues typically macrodomains, MacroD1, MacroD2, terminal 1 (24Barkauskaite Jankevicius G. Structures synthesis degradation PARP-dependent ADP-ribosylation.Mol. Cell. 2015; 935-946Abstract (190) acids. phosphate-linked reversed 1, (9Schuller adenine-linked removed There still much work establish However, elucidated regulated strand breaks, potent stimulator production cells. Indeed, abundant enzyme primary writer cell, output accounts approximately 80 90% produced (25D'Amours Desnoyers D'Silva Poirier G.G. reactions regulation nuclear functions.Biochem. 1999; 342: 249-268Crossref (1612) domain architecture six independently folded domains: (Zn1, Zn2, Zn3), WGR (Trp-Gly-Arg) domain, (CAT) domain. CAT helical (HD) ART located localizes nucleus where scans intact chromatin intrastrand transfer, monkey-bar (26Rudolph Mahadevan Dyer Luger Poly(ADP-ribose) searches 'monkey bar' mechanism.Elife. 7e37818Crossref (42) transfer cooperative fingers, move molecule another 27Rudolph Muthurajan U.M. Palacio Roberts Erbse A.H. binds transfer.Mol. 81: 4994-5006.e5Abstract scanning does trigger (27Rudolph 28Benjamin R.C. Gill D.M. programmed damaged comparison different types breaks.J. 1980; 255: 10502-10508Abstract Rather, activated following efficient organization (29Langelier M.F. Planck J.L. Roy Pascal Structural basis damage-dependent poly(ADP-ribosyl)ation PARP-1.Science. 2012; 336: 728-732Crossref (465) 30Eustermann Wu W.F. Langelier Easton L.E. Riccio A.A. al.Structural detection single-strand breaks PARP-1.Mol. 60: 742-754Abstract (202) 31Rudolph Probing conformational changes associated PARP1.Biochemistry. 59: 2003-2011Crossref relays activating signal allosteric communication opens HD, relieving autoinhibitory (32Dawicki-McKenna DeNizio J.E. Cao C.D. Karch K.R. al.PARP-1 activation local unfolding domain.Mol. 755-768Abstract (204) causes additional WGR-HD interface concomitant concerted rotation (33Rouleau-Turcotte É. Krastev D.B. Pettitt Lord C.J. Captured snapshots state reveal mechanics allostery.Mol. 82: 2939-2951.e5Abstract 2). recognition sequence-dependent allows (SSBs), double-strand (DSBs), even apurinic apyrimidinic integrity backbone preserved 34Khodyreva S.N. Prasad Ilina Sukhanova M.V. Kutuzov M.M. al.Apurinic/apyrimidinic (AP) 5'-dRP/AP lyase polymerase-1 (PARP-1).Proc. Natl. Acad. Sci. U. 107: 22090-22095Crossref contributes chromatin, appear On own, catalytically primarily modifies aspartate glutamate so-called "automodification region" fold nearby linker region (35Ayyappan Wat Barber Vivelo C.A. Gauch Visanpattanasin al.ADPriboDB 2.0: updated database ADP-ribosylated D261-D265Crossref (5) trans other proteins. During DDR, undergoes change specificity collaborates cofactor (HPF1) modify serine histones itself (36Bonfiglio Fontana Zhang Colby Gibbs-Seymour Atanassov al.Serine depends HPF1.Mol. 932-940.e6Abstract (210) newfound ability Ser due joint HPF1, greatly favored HD opening, HPF1 inserts Glu residue deprotonate acceptor initiate (37Suskiewicz Zobel Ogden T.E.H. al.HPF1 completes damage-induced ADP-ribosylation.Nature. 579: 598-602Crossref (139) 38Sun F.H. Zhao Kong L.L. Wong C.C.L. Yun C.H. remodels enable histones.Nat. 1028Crossref (38) being less relies "hit run" form substochiometric ratios (39Langelier Billur Sverzhinsky Black B.E. dynamically controls PARP1/2 initiating elongating modifications.Nat. 6675Crossref (27) Despite short-lived interaction, speeds up initial events reduces sterically blocks Ser-linked appears shorter Glu/Asp-linked modulates shifting Ser-ADP-ribosylation relative automodification 40Gibbs-Seymour HPF1/C4orf27 PARP-1-interacting regulates PARP-1 activity.Mol. 2016; 62: 432-442Abstract (184) ultimately (41Palazzo Leidecker Prokhorova Dauben H. major upon damage.Elife. 7e34334Crossref (63) Overall, burst initiates recruits (i.e., readers). While steered automodifies residues, namely S499, S507, S519 (42Prokhorova Smith Zentout Schutzenhofer al.Serine-linked auto-modification inhibitor response.Nat. 4055Crossref (44) Mutating was shown retain longer suggesting likely needed timely release process. highly negatively charged PTM, charge repulsion driving force (43Murai Huang S.Y. Das B.B. Renaud Doroshow J.H. al.Trapping clinical inhibitors.Cancer 72: 5588-5599Crossref (1497) 44Murai Ji Takeda al.Stereospecific BMN 673 olaparib rucaparib.Mol. Cancer Ther. 2014; 433-443Crossref (565) enacting possible. Another well-studied member closest homolog contrast only short, unstructured N-terminal (NTR) accompany (45Riccio Cingolani PARP-2 requirements localization damage.Nucleic 44: 1691-1702Crossref Also, unlike navigates chromatin. mostly mediated 5′ (46Langelier PARP-3 selective

Language: Английский

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PARP14 is a writer, reader, and eraser of mono-ADP-ribosylation

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(9), P. 105096 - 105096

Published: July 26, 2023

PARP14/BAL2 is a large multidomain enzyme involved in signaling pathways with relevance to cancer, inflammation, and infection. Inhibition of its mono-ADP-ribosylating PARP homology domain three ADP-ribosyl binding macro domains has been regarded as potential means therapeutic intervention. Macrodomains-2 -3 are known stably bind ADP-ribosylated target proteins, but the function macrodomain-1 remained somewhat elusive. Here, we used biochemical assays ADP-ribosylation levels characterize PARP14 homologous PARP9. Our results show that both macrodomains display an glycohydrolase activity not directed toward specific protein side chains. unable degrade poly(ADP-ribose), enzymatic product PARP1. The F926A mutation F244A PARP9 strongly reduced respective macrodomains, suggesting mechanistic Mac1 SARS-CoV-2 Nsp3 protein. This study adds two new enzymes previously six human glycohydrolases. have key implications for how will be studied their functions understood.

Language: Английский

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PARPs and ADP-ribosylation-mediated biomolecular condensates: determinants, dynamics, and disease implications

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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An ADP-ribosyltransferase toxin kills bacterial cells by modifying structured non-coding RNAs

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(18), P. 3484 - 3498.e11

Published: Sept. 1, 2022

Language: Английский

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Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors

Pathogens, Journal Year: 2023, Volume and Issue: 12(2), P. 324 - 324

Published: Feb. 15, 2023

The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight importance of increasing preparedness for viral disease outbreaks providing rapid prevention treatment strategies. NSP3 macrodomain coronaviruses including SARS-CoV-2 is among protein repertoire that was identified as a potential target development antiviral agents, due to its critical role in replication consequent pathogenicity host. By combining virtual biophysical screening efforts, we discovered several experimental small molecules FDA-approved drugs inhibitors macrodomain. Analogue characterisation hit matter crystallographic studies confirming binding modes, antibiotic compound aztreonam, active site provide valuable structure–activity relationship information support current approaches open up new avenues inhibitor development.

Language: Английский

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Specificity of DNA ADP-Ribosylation Reversal by NADARs

Toxins, Journal Year: 2024, Volume and Issue: 16(5), P. 208 - 208

Published: April 28, 2024

Recent discoveries establish DNA and RNA as bona fide substrates for ADP-ribosylation. NADAR (“NAD- ADP-ribose”-associated) enzymes reverse guanine ADP-ribosylation serve antitoxins in the DarT-NADAR operon. Although NADARs are widespread across prokaryotes, eukaryotes, viruses, their specificity broader physiological roles remain poorly understood. Using phylogenetic biochemical analyses, we further explore de-ADP-ribosylation activity antitoxin functions of domains. We demonstrate that different subfamilies proteins from representative E. coli strains an coli-infecting phage retain while displaying providing protection toxic cells. Furthermore, identify a myxobacterial enzyme within YbiA subfamily its associated DarT-unrelated ART toxin, which termed YarT, thus presenting hitherto uncharacterised ART-YbiA toxin–antitoxin pair. Our studies contribute to burgeoning field ADP-ribosylation, supporting relevance beyond bacterial systems. Notably, confinement non-mammals infer potential highly specific targets antimicrobial drugs with minimal off-target effects.

Language: Английский

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Apprehending the NAD+–ADPr-Dependent Systems in the Virus World

Viruses, Journal Year: 2022, Volume and Issue: 14(9), P. 1977 - 1977

Published: Sept. 7, 2022

NAD+ and ADP-ribose (ADPr)-containing molecules are at the interface of virus-host conflicts across life encompassing RNA processing, restriction, lysogeny/dormancy functional hijacking. We objectively defined central components NAD+-ADPr networks involved in these systematically surveyed 21,191 completely sequenced viral proteomes representative all publicly available branches world to reconstruct a comprehensive picture systems. These systems have been widely repeatedly exploited by positive-strand DNA viruses, especially those with larger genomes more intricate life-history strategies. present evidence that ADP-ribosyltransferases (ARTs), ADPr-targeting Macro, NADAR Nudix proteins frequently packaged into virions, particularly phages contractile tails (Myoviruses), deployed during infection modify host macromolecules counter NAD+-derived signals restriction. Genes encoding NAD+-ADPr-utilizing domains were exchanged between distantly related hosts endo-parasites/symbionts, suggesting selection for them virus world. Contextual analysis indicates bacteriophage versions likely soluble ADPr derivatives, while eukaryotic might prefer macromolecular adducts. Finally, we also use comparative genomics predict countering ADP ribosylation molecules.

Language: Английский

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