ADP-ribosylation from molecular mechanisms to therapeutic implications

Cell, Год журнала: 2023, Номер 186(21), С. 4475 - 4495

Опубликована: Окт. 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.

Язык: Английский

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PARP1-DNA co-condensation drives DNA repair site assembly to prevent disjunction of broken DNA ends

Cell, Год журнала: 2024, Номер 187(4), С. 945 - 961.e18

Опубликована: Фев. 1, 2024

DNA double-strand breaks (DSBs) are repaired at DSB sites. How sites assemble and how broken is prevented from separating not understood. Here we uncover that the synapsis of mediated by sensor protein poly(ADP-ribose) (PAR) polymerase 1 (PARP1). Using bottom-up biochemistry, reconstitute functional show form through co-condensation PARP1 multimers with DNA. The co-condensates exert mechanical forces to keep ends together become enzymatically active for PAR synthesis. PARylation promotes release recruitment effectors, such as Fused in Sarcoma, which stabilizes against separation, revealing a finely orchestrated order events primes repair. We provide comprehensive model hierarchical assembly condensates explain end effector proteins damage

Язык: Английский

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Parps in immune response: Potential targets for cancer immunotherapy

Biochemical Pharmacology, Год журнала: 2025, Номер 234, С. 116803 - 116803

Опубликована: Фев. 16, 2025

Язык: Английский

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The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment

Journal of Hematology & Oncology, Год журнала: 2022, Номер 15(1)

Опубликована: Окт. 17, 2022

Abstract Continuous cell division is a hallmark of cancer, and the underlying mechanism tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly maintaining genome stability during division. Based on their distinct functions in control, classified into two groups: DNA damage replication stress checkpoints. The (ATM-CHK2-p53) primarily monitor genetic errors arrest progression to facilitate repair. Unfortunately, genes involved frequently mutated human malignancies. In contrast, associated with (ATR-CHK1-WEE1) rarely tumors, cancer cells highly dependent these prevent catastrophe secure integrity. At present, poly (ADP-ribose) polymerase inhibitors (PARPi) operate through “synthetic lethality” mutant repair pathways cells. However, increasing number patients acquiring PARP inhibitor resistance after prolonged treatment. Recent work suggests that combination therapy targeting PARPs act synergistically increase errors, compromise machinery, disrupt cycle, thereby death rate deficiency or resistance. We highlight combinational strategy involving inhibition major checkpoint pathways, ATM-CHK2-TP53 ATR-CHK1-WEE1. biological functions, mechanisms against inhibitors, advances preclinical research, clinical trials also reviewed.

Язык: Английский

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Clinical PARP inhibitors allosterically induce PARP2 retention on DNA

Science Advances, Год журнала: 2023, Номер 9(12)

Опубликована: Март 24, 2023

PARP1 and PARP2 detect DNA breaks, which activates their catalytic production of poly(ADP-ribose) that recruits repair factors contributes to PARP1/2 release from DNA. PARP inhibitors (PARPi) are used in cancer treatment target activity, interfering with increasing persistence on damage. In addition, certain PARPi exert allosteric effects increase retention However, no clinical exhibit this behavior toward PARP1. contrast, we show an effect retains breaks a manner depends communication between the binding regions. Using mutant mimics inhibitor effect, observed increased at cellular damage sites. The AZD5305 also exhibited clear reverse PARP2. Our results can help explain toxicity suggest ways improve moving forward.

Язык: 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, Год журнала: 2023, Номер 299(12), С. 105397 - 105397

Опубликована: Окт. 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

Язык: Английский

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Specific and shared biological functions of PARP2 – is PARP2 really a lil’ brother of PARP1?

Expert Reviews in Molecular Medicine, Год журнала: 2024, Номер 26

Опубликована: Янв. 1, 2024

Abstract PARP2, that belongs to the family of ADP-ribosyl transferase enzymes (ART), is a discovery millennium, as it was identified in 1999. Although PARP2 described initially DNA repair factor, now evident partakes regulation or execution multiple biological processes inflammation, carcinogenesis and cancer progression, metabolism oxidative stress-related diseases. Hereby, we review involvement these with aim understanding which are specific for but not other members ART family. A better functions all crucial development new PARP-centred selective therapies.

Язык: Английский

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The dynamics and regulation of PARP1 and PARP2 in response to DNA damage and during replication

DNA repair, Год журнала: 2024, Номер 140, С. 103690 - 103690

Опубликована: Май 25, 2024

Язык: Английский

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Poly(ADP-Ribose) Polymerase (PARP) Inhibitors for Cancer Therapy: Advances, Challenges, and Future Directions

Biomolecules, Год журнала: 2024, Номер 14(10), С. 1269 - 1269

Опубликована: Окт. 9, 2024

Poly(ADP-ribose) polymerases (PARPs) are crucial nuclear proteins that play important roles in various cellular processes, including DNA repair, gene transcription, and cell death. Among the 17 identified PARP family members, PARP1 is most abundant enzyme, with approximately 1-2 million molecules per cell, acting primarily as a damage sensor. It has become promising biological target for anticancer drug studies. Enhanced expression present several types of tumors, such melanomas, lung cancers, breast correlating low survival outcomes resistance to treatment. inhibitors, especially newly developed third-generation inhibitors currently undergoing Phase II clinical trials, have shown efficacy agents both single drugs sensitizers chemo- radiotherapy. This review explores properties, characteristics, challenges discussing their development from first-generation compounds, more sustainable synthesis methods discovery new anti-cancer agents, mechanisms therapeutic action, potential targeting additional targets beyond catalytic active site proteins. Perspectives on green chemistry also discussed.

Язык: Английский

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Inactive PARP1 causes embryonic lethality and genome instability in a dominant-negative manner

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(31)

Опубликована: Июль 24, 2023

PARP1 (poly-ADP ribose polymerase 1) is recruited and activated by DNA strand breaks, catalyzing the generation of poly-ADP-ribose (PAR) chains from NAD+. PAR relaxes chromatin recruits other repair factors, including XRCC1 Ligase 3, to maintain genomic stability. Here we show that, in contrast normal development Parp1-null mice, heterozygous expression catalytically inactive Parp1 (E988A,

Язык: Английский

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