ADP-ribosylation from molecular mechanisms to therapeutic implications

Cell, Journal Year: 2023, Volume and Issue: 186(21), P. 4475 - 4495

Published: Oct. 1, 2023

ADP-ribosylation is a ubiquitous modification of biomolecules, including proteins and nucleic acids, that regulates various cellular functions in all kingdoms life. The recent emergence new technologies to study has reshaped our understanding the molecular mechanisms govern establishment, removal, recognition this modification, as well its impact on organismal function. These advances have also revealed intricate involvement human physiology pathology enormous potential their manipulation holds for therapy. In review, we present state-of-the-art findings covering work structural biology, biochemistry, cell clinical aspects ADP-ribosylation.

Language: Английский

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PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(14), P. 2929 - 2953

Published: June 4, 2024

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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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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RACK1 MARylation regulates translation and stress granules in ovarian cancer cells

The Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 224(2)

Published: Jan. 6, 2025

Mono(ADP-ribosyl)ation (MARylation) is emerging as a critical regulator of ribosome function and translation. Herein, we demonstrate that RACK1, an integral component the ribosome, MARylated by mono(ADP-ribosyl) transferase (MART) PARP14 in ovarian cancer cells. MARylation RACK1 required for stress granule formation promotes colocalization granules with G3BP1, eIF3η, 40S ribosomal proteins. In parallel, observed reduced translation subset mRNAs, including those encoding key regulators (e.g., AKT). Treatment inhibitor or mutation sites on blocks these outcomes, well growth cells culture vivo. To reset system after prolonged recovery, ADP-ribosyl hydrolase TARG1 deMARylates leading to dissociation restoration Collectively, our results therapeutically targetable pathway controls polysome assembly, translation, dynamics

Language: Английский

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PARP enzymes and mono-ADP-ribosylation: advancing the connection from interferon-signalling to cancer biology

Expert Reviews in Molecular Medicine, Journal Year: 2024, Volume and Issue: 26

Published: Jan. 1, 2024

Abstract ADP-ribosyltransferases of the PARP family encompass a group enzymes with variegated regulatory functions in cells, ranging from DNA damage repair to control cell-cycle progression and immune response. Over years, this knowledge has led use PARP1/2 inhibitors as mainstay pharmaceutical strategies for treatment ovarian, pancreatic, prostate breast cancers, holding mutations genes encoding proteins involved mechanisms (synthetic lethality). Meanwhile, last decade witnessed significant progress comprehending cellular pathways regulated by mono-ADP-ribosylation, huge effort development novel selective compounds inhibit those PARPs endowed mono-ADP-ribosylation activity. This review focuses on achieved cancer field, delving into most recent findings regarding role subset – interferon-stimulated progression.

Language: Английский

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A PARP14/TARG1-Regulated RACK1 MARylation Cycle Drives Stress Granule Dynamics in Ovarian Cancer Cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 14, 2023

Abstract Mono(ADP-ribosyl)ation (MARylation) is emerging as a critical regulator of ribosome function and translation. Herein, we demonstrate that RACK1, an integral component the ribosome, MARylated on three acidic residues by mono(ADP-ribosyl) transferase (MART) PARP14 in ovarian cancer cells. MARylation RACK1 required for stress granule formation promotes colocalization granules with G3BP1, eIF3η, 40S ribosomal proteins. In parallel, observed reduced translation subset mRNAs, including those encoding key regulators (e.g., AKT). Treatment inhibitor or mutation sites blocks these outcomes, well growth cells culture vivo. To re-set system after prolonged recovery, ADP-ribosyl hydrolase TARG1 deMARylates leading to dissociation restoration Collectively, our results therapeutically targetable pathway controls assembly disassembly Summary We have discovered druggable PARP14/TARG1-regulated mediates site- specific mono(ADP-ribosyl)ation protein. This disassembly, modulate

Language: Английский

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Privileged Scaffolds for Potent and Specific Inhibitors of Mono-ADP-Ribosylating PARPs

Molecules, Journal Year: 2023, Volume and Issue: 28(15), P. 5849 - 5849

Published: Aug. 3, 2023

The identification of new targets to address unmet medical needs, better in a personalized way, is an urgent necessity. introduction PARP1 inhibitors into therapy, almost ten years ago, has represented step forward this need being innovate cancer treatment through precision medicine approach. PARP family consists 17 members which that works by poly-ADP ribosylating the substrate sole enzyme so far exploited as therapeutic target. Most other are mono-ADP-ribosylating (mono-ARTs) enzymes, and recent studies have deciphered their pathophysiological roles appear be very extensive with various potential applications. In parallel, handful mono-ARTs emerged been collected perspective on 2022. After that, additional interesting compounds were identified highlighting hot-topic nature research field prompting update. From present review, where we reported only endowed appropriate profile pharmacological tools or drug candidate, four privileged scaffolds clearly stood out constitute basis for further discovery campaigns.

Language: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 4, 2024

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

Language: Английский

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Pathological and physiological roles of ADP-ribosylation: established functions and new insights

Biological Chemistry, Journal Year: 2024, Volume and Issue: 405(9-10), P. 567 - 581

Published: July 26, 2024

Abstract The posttranslational modification of proteins with poly(ADP-ribose) was discovered in the sixties. Since then, we have learned that enzymes involved, so-called poly(ADP-ribosyl)polymerases (PARPs), are transferases which use cofactor NAD + to transfer ADP-ribose their targets. Few PARPs able create poly(ADP-ribose), whereas majority transfers a single ADP-ribose. In last decade, hydrolases were reverse mono(ADP-ribosyl)ation, detection methods developed and new substrates defined, including nucleic acids. Despite continued effort, relatively little is still known about biological function most PARPs. this review, summarise key functions ADP-ribosylation introduce emerging insights.

Language: Английский

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