Inhibitors of PARP: Number crunching and structure gazing

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(11)

Published: March 8, 2022

SignificancePARP is an important target in the treatment of cancers, particularly patients with breast, ovarian, or prostate cancer that have compromised homologous recombination repair (i.e., BRCA

Language: Английский

---

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

---

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

Cell, Journal Year: 2024, Volume and Issue: 187(4), P. 945 - 961.e18

Published: Feb. 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

Language: Английский

---

PARP1: Liaison of Chromatin Remodeling and Transcription

Cancers, Journal Year: 2022, Volume and Issue: 14(17), P. 4162 - 4162

Published: Aug. 27, 2022

Poly(ADP-ribosyl)ation (PARylation) is a covalent post-translational modification and plays key role in the immediate response of cells to stress signals. Poly(ADP-ribose) polymerase 1 (PARP1), founding member PARP superfamily, synthesizes long branched polymers ADP-ribose (PAR) onto acceptor proteins, thereby modulating their function local surrounding. PARP1 most prominent PARPs responsible for production about 90% PAR cell. Therefore, PARylation play pleotropic wide range cellular processes, such as DNA repair genomic stability, cell death, chromatin remodeling, inflammatory gene transcription. has DNA-binding catalytic activities that are important repair, yet also modulate conformation transcription, which can be independent damage response. homeostasis have been implicated multiple diseases, including inflammation, stroke, diabetes cancer. Studies molecular action biological provide basis development pharmaceutic strategies clinical applications. This review focuses primarily on regulation remodeling transcriptional activation.

Language: Английский

---

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

---

Clinical PARP inhibitors allosterically induce PARP2 retention on DNA

Science Advances, Journal Year: 2023, Volume and Issue: 9(12)

Published: March 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.

Language: Английский

---

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

---

Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 228, P. 116174 - 116174

Published: March 27, 2024

Language: Английский

---

A review of poly(ADP-ribose)polymerase-1 (PARP1) role and its inhibitors bearing pyrazole or indazole core for cancer therapy

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 221, P. 116045 - 116045

Published: Feb. 8, 2024

Cancer is a disease with high mortality rate characterized by uncontrolled proliferation of abnormal cells. The hallmarks cancer evidence the acquired cells characteristics that promote growth malignant tumours, including genomic instability and mutations, ability to evade cellular death capacity sustaining proliferative signalization. Poly(ADP-ribose) polymerase-1 (PARP1) protein plays key roles in regulation, namely DNA damage repair cell survival. inhibition PARP1 promotes homologous recombination deficiency, therefore, interest PARP has been rising as target for anticancer therapies. There are already some inhibitors approved Food Drug Administration (FDA), such Olaparib Niraparib. last compound presents its structure an indazole core. In fact, pyrazoles indazoles have raising due their various medicinal properties, namely, activity. Derivatives these compounds studied presented promising results. Therefore, this review aims address importance regulation role cancer. Moreover, it intends report comprehensive literature inhibitors, containing pyrazole scaffolds, published fifteen years, focusing on structure-activity relationship aspects, thus providing important insights design novel more effective inhibitors.

Language: Английский

---

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

DNA repair, Journal Year: 2024, Volume and Issue: 140, P. 103690 - 103690

Published: May 25, 2024

Language: Английский

---