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

---

Poly ADP-Ribosylation in a Plant Pathogenic Oomycete Phytophthora infestans: A Key Controller of Growth and Host Plant Colonisation

Journal of Fungi, Год журнала: 2025, Номер 11(1), С. 29 - 29

Опубликована: Янв. 3, 2025

ADP-ribosylation is a reversible modification of proteins and nucleic acids, which controls major cellular processes, including DNA damage repair, cell proliferation differentiation, metabolism, stress, immunity in plants animals. The involvement the life cycle Dictyostelium some filamentous fungi has also been demonstrated. However, role this process pathogenic oomycetes never addressed. Here, we show that Phytophthora infestans genome contains two PARP-like protein genes (PiPARP1 PiPARP2), provide evidence PARylation activity for one them (PiPARP2). Using dsRNA-mediated RNA silencing PiPARP2 gene chemical (pharmacological) inhibition PARP by 3-aminobenzamide (3AB) inhibitor, demonstrate critical functional mycelium growth. Virulence test on detached leaves suggests an important host plant colonisation pathogenesis. On practical level, our data suggest targeting system may constitute novel powerful approach management diseases.

Язык: Английский

---

A Theoretical Study on the Efficacy and Mechanism of Combined YAP-1 and PARP-1 Inhibitors in the Treatment of Glioblastoma Multiforme Using Peruvian Maca Lepidium meyenii

Current Issues in Molecular Biology, Год журнала: 2025, Номер 47(1), С. 40 - 40

Опубликована: Янв. 9, 2025

Glioblastoma multiforme (GBM) is one of the most aggressive and treatment-resistant forms brain cancer. Current therapeutic strategies, including surgery, chemotherapy, radiotherapy, often fail due to tumor’s ability develop resistance. The proteins YAP-1 (Yes-associated protein 1) PARP-1 (Poly-(ADP-ribose)–polymerase-1) have been implicated in this resistance, playing crucial roles cell proliferation DNA repair mechanisms, respectively. This study explored inhibitory potential natural compounds from Lepidium meyenii (Peruvian Maca) on systems novel strategies for GBM. By molecular dynamics simulations, we identified N-(3-Methoxybenzyl)-(9Z,12Z,15Z)- octadecatrienamide (DK5) as promising inhibitor stearic acid (GK4) YAP-1. Although synthetic inhibitors, such Olaparib (ODK) Verteporfin (VER) YAP-1, only VER was superior naturally occurring molecule proved a alternative. In conclusion, offer potentially innovative approach improve GBM treatment, complementing existing therapies with their action

Язык: Английский

---

PARP1: A comprehensive review of its mechanisms, therapeutic implications and emerging cancer treatments

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2025, Номер unknown, С. 189282 - 189282

Опубликована: Фев. 1, 2025

Язык: Английский

---

PARP1-dependent DNA-protein crosslink repair

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 5, 2024

DNA-protein crosslinks (DPCs) are toxic lesions that inhibit DNA related processes. Post-translational modifications (PTMs), including SUMOylation and ubiquitylation, play a central role in DPC resolution, but whether other PTMs also involved remains elusive. Here, we identify repair pathway orchestrated by poly-ADP-ribosylation (PARylation). Using Xenopus egg extracts, show DPCs on single-stranded gaps can be targeted for degradation via replication-independent mechanism. During this process, initially PARylated PARP1 subsequently ubiquitylated degraded the proteasome. Notably, PARP1-mediated resolution is required resolving topoisomerase 1-DNA cleavage complexes (TOP1ccs) induced camptothecin. Flp-nick system, further reveal absence of activity, TOP1cc-like lesion persists induces replisome disassembly when encountered replication fork. In summary, our work uncovers may underlie synergistic toxicity between TOP1 poisons PARP inhibitors. The authors crosslink (DPC) poly-ADP-ribosylation. PARylates DPC, marking it removal proteolysis. Consequently, facilitates located next to breaks, such as 1-DPCs.

Язык: Английский

---

Targeting selective inhibitors of PARPs in drug discovery and development

Medicinal Chemistry Research, Год журнала: 2024, Номер 33(10), С. 1734 - 1756

Опубликована: Июль 28, 2024

Язык: Английский

---

A Comprehensive Review on PARP Inhibitors in Targeted Therapy for Cancers

Deleted Journal, Год журнала: 2024, Номер 19(2), С. 44 - 59

Опубликована: Авг. 9, 2024

The poly (ADP-ribose) polymerase (PARP) family of enzymes involves and regulates various cellular processes essential functions, such as apoptosis, transcription process, DNA repair. PARPs (PARP-1, PARP-2, PARP-3) are a branch familiar proteins that play crucial role in repairing damage human gene involved different cancers regulate the base excision repair (BER) pathway. As target-based drug therapy for cancer, inhibition PARP stops PARP-1 -2 from damaged mutated cancer cells, eventually, cells die. Considering limited available therapies treatment advanced recurrent cancers, inhibitors (PARPi) first approved drugs particularly target response to BRCA (BReast CAncer gene)-1/2 ovarian, pancreatic, prostate, breast cancers. Recently, six PARPi viz., olaparib, rucaparib, niraparib, talazoparib, fuzuloparib, pamiparib were monotherapy or combination with other classes anticancer agents maintenance Moreover, appears improve progression-free survival women platinum-sensitive ovarian an adjuvant conventional treatment. Importantly, use management germline BRCA1/2-associated is novel therapeutic strategy, representing successful targeted improving outcomes patients hereditary Although resistance these has been reported recently, however, strategies have employed overcome sensitivity breast, gastric, prostate

Язык: Английский

---

The dynamic process of covalent and non-covalent PARylation in the maintenance of genome integrity: a focus on PARP inhibitors

NAR Cancer, Год журнала: 2023, Номер 5(3)

Опубликована: Июнь 9, 2023

Abstract Poly(ADP-ribosylation) (PARylation) by poly(ADP-ribose) polymerases (PARPs) is a highly regulated process that consists of the covalent addition polymers ADP-ribose (PAR) through post-translational modifications substrate proteins or non-covalent interactions with PAR via binding domains and motifs, thereby reprogramming their functions. This modification particularly known for its central role in maintenance genomic stability. However, how integrity controlled an intricate interplay PARylation remains largely unknown. Of importance, has caught recent attention providing mechanistic basis synthetic lethality involving PARP inhibitors (PARPi), most notably homologous recombination (HR)-deficient breast ovarian tumors. The molecular mechanisms responsible anti-cancer effect PARPi are thought to implicate both catalytic inhibition trapping enzymes on DNA. relative contribution each tumor-specific cytotoxicity still unclear. It paramount understand these PAR-dependent mechanisms, given resistance challenge clinic. Deciphering complex between defining non-trapping events contribute anti-tumour activity essential developing improved therapeutic strategies. With this perspective, we review current understanding biology context DNA damage response (DDR) underlying resistance.

Язык: Английский

---

New Perspectives on the Role of Nuclear Proteases in Cell Death Pathways

Biology, Год журнала: 2023, Номер 12(6), С. 797 - 797

Опубликована: Май 31, 2023

Multiple factors can trigger cell death via various pathways, and nuclear proteases have emerged as essential regulators of these processes. While certain been extensively studied their mechanisms action are well understood, others remain poorly characterized. Regulation protease activity is a promising therapeutic strategy that could selectively induce favorable pathways in specific tissues or organs. Thus, by understanding the roles newly discovered predicted processes, we identify new pharmacological targets for improving outcomes. In this article, delved into role several types explore potential avenues future research development.

Язык: Английский

---

Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming

Antioxidants, Год журнала: 2023, Номер 12(10), С. 1790 - 1790

Опубликована: Сен. 22, 2023

Macrophage polarization is highly involved in autoimmunity. M1 polarized macrophages drive inflammation and undergo metabolic reprogramming, involving downregulation of mitochondrial energy production acceleration glycolysis. migration inhibitory factor (MIF), an enigmatic tautomerase (ketonase enolase), was discovered to regulate polarization. Here, we reveal that KRP-6, a potent selective MIF ketonase inhibitor, reduces MIF-induced human blood eosinophil neutrophil similarly ISO-1, the most investigated inhibitor. We equally KRP-6 prevents macrophage ROS IFN-γ-treated cells. During improved bioenergetics by ameliorating basal respiration, ATP production, coupling efficiency maximal respiration LPS+IFN-γ-treated also reduced glycolytic flux macrophages. Moreover, inhibitor attenuated LPS+IFN-γ-induced PARP-1 PARP-2 mRNA expression. conclude represents promising novel therapeutic compound for autoimmune diseases, which strongly involves

Язык: Английский

---