Polybrominated Diphenyl Ethers Quinone Induced Parthanatos-like Cell Death through a Reactive Oxygen Species-Associated Poly(ADP-ribose) Polymerase 1 Signaling
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Polybrominated diphenyl ethers (PBDEs) are emerging organic environmental pollutants, which were accused of various toxic effects. Here, we studied the role of a potential PBDEs quinone metabolite, PBDEQ, on cytotoxicity, oxidative DNA damage, and the alterations of signal cascade in HeLa cells. PBDEQ exposure leads to reactive oxygen species (ROS) accumulation, mitochondrial membrane potential (MMP) loss, lactate dehydrogenase (LDH) release, increasing terminal transferase-mediated dUTP-biotin nick end labeling (TUNEL) positive foci, and the elevation of apoptosis rate. Furthermore, we showed PBDEQ exposure result in increased DNA migration, micronucleus frequency, and the promotion of 8-OHdG and phosphorylation of histone H2AX (γ-H2AX) levels. Mechanism study indicated that PBDEQ caused poly(ADP-ribose) polymerase 1 (PARP-1) activation and apoptosis-inducing factor (AIF) nuclear translocation. All together, these results confirmed the occurrence of parthanatos-like cell death upon PBDEQ exposure.Keywords:
PARP1
HeLa
Ribose
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ADP-ribose is a versatile modification that plays a critical role in diverse cellular processes. The addition of this modification is catalyzed by ADP-ribosyltransferases, among which notable poly(ADP-ribose) polymerase (PARP) enzymes are intimately involved in the maintenance of genome integrity. The role of ADP-ribose modifications during DNA damage repair is of significant interest for the proper development of PARP inhibitors targeted toward the treatment of diseases caused by genomic instability. More specifically, inhibitors promoting PARP persistence on DNA lesions, termed PARP "trapping," is considered a desirable characteristic. In this review, we discuss key classes of proteins involved in ADP-ribose signaling (writers, readers, and erasers) with a focus on those involved in the maintenance of genome integrity. An overview of factors that modulate PARP1 and PARP2 persistence at sites of DNA lesions is also discussed. Finally, we clarify aspects of the PARP trapping model in light of recent studies that characterize the kinetics of PARP1 and PARP2 recruitment at sites of lesions. These findings suggest that PARP trapping could be considered as the continuous recruitment of PARP molecules to sites of lesions, rather than the physical stalling of molecules. Recent studies and novel research tools have elevated the level of understanding of ADP-ribosylation, marking a coming-of-age for this interesting modification. ADP-ribose is a versatile modification that plays a critical role in diverse cellular processes. The addition of this modification is catalyzed by ADP-ribosyltransferases, among which notable poly(ADP-ribose) polymerase (PARP) enzymes are intimately involved in the maintenance of genome integrity. The role of ADP-ribose modifications during DNA damage repair is of significant interest for the proper development of PARP inhibitors targeted toward the treatment of diseases caused by genomic instability. More specifically, inhibitors promoting PARP persistence on DNA lesions, termed PARP "trapping," is considered a desirable characteristic. In this review, we discuss key classes of proteins involved in ADP-ribose signaling (writers, readers, and erasers) with a focus on those involved in the maintenance of genome integrity. An overview of factors that modulate PARP1 and PARP2 persistence at sites of DNA lesions is also discussed. Finally, we clarify aspects of the PARP trapping model in light of recent studies that characterize the kinetics of PARP1 and PARP2 recruitment at sites of lesions. These findings suggest that PARP trapping could be considered as the continuous recruitment of PARP molecules to sites of lesions, rather than the physical stalling of molecules. Recent studies and novel research tools have elevated the level of understanding of ADP-ribosylation, marking a coming-of-age for this interesting modification. DNA carries the necessary information for many processes within the cell and maintaining its stability is of critical importance to ensure cell viability. Genome instability can arise from endogenous causes, such as normal genome transactions (replication, transcription, recombination), but also from exogenous causes, like external genome damaging agents (1Chatterjee N. Walker G.C. Mechanisms of DNA damage, repair, and mutagenesis.Environ. Mol. Mutagen. 2017; 58: 235-263Crossref PubMed Scopus (957) Google Scholar). The sheer number of lesions each human cell experiences daily (approximately 70,000 lesions) (2Lindahl T. Barnes D.E. Repair of endogenous DNA damage.Cold Spring Harb. Symp. Quant. Biol. 2000; 65: 127-133Crossref PubMed Google Scholar) highlights the heavy demand put on genome maintenance mechanisms. As such, a variety of DNA repair pathways exist to tackle the diversity and abundance of lesions, with many of these pathways carrying overlapping functions (1Chatterjee N. Walker G.C. Mechanisms of DNA damage, repair, and mutagenesis.Environ. Mol. Mutagen. 2017; 58: 235-263Crossref PubMed Scopus (957) Google Scholar). DNA repair pathways rely on the interplay between enzymes and posttranslational modifications (PTMs) (phosphorylation, ubiquitylation, SUMOylation, etc) to proceed with success (3Huen M.S. Chen J. The DNA damage response pathways: at the crossroad of protein modifications.Cell Res. 2008; 18: 8-16Crossref PubMed Scopus (162) Google Scholar). ADP-ribose is an ancient protein and nucleic acid modification that has been utilized in many organisms, often as a defense mechanism (4Lüscher B. Bütepage M. Eckei L. Krieg S. Verheugd P. Shilton B.H. ADP-ribosylation, a multifaceted posttranslational modification involved in the control of cell physiology in health and disease.Chem. Rev. 2018; 118: 1092-1136Crossref PubMed Scopus (154) Google Scholar). Mammalian cells employ ADP-ribose modifications in a variety of cellular contexts, including antiviral defense/innate immunity, protein homeostasis, gene regulation, and DNA repair/genome maintenance (5Luscher B. Ahel I. Altmeyer M. Ashworth A. Bai P. Chang P. et al.ADP-ribosyltransferases, an update on function and nomenclature.FEBS J. 2021; 289: 7399-7410Crossref PubMed Scopus (104) Google Scholar). Notably, in addition to single ADP-ribose (ADPr) unit modifications, multiple ADPr can be joined in a polymer known as poly(ADP-ribose) or PAR. PAR chains can be linearly elongated through the formation of a (2′-1″) ribose–ribose glycosidic bond between ADPr units. Occasionally, a (2″-1″) ribose–ribose bond can occur which branches the polymer (Fig. 1A) (6Chen Q. Kassab M.A. Dantzer F. Yu X. PARP2 mediates branched poly ADP-ribosylation in response to DNA damage.Nat. Commun. 2018; 9: 3233Crossref PubMed Scopus (97) Google Scholar, 7Alemasova E.E. Lavrik O.I. Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins.Nucleic Acids Res. 2019; 47: 3811-3827Crossref PubMed Scopus (232) Google Scholar). Although the majority of published studies have investigated ADPr modification of proteins, there is growing evidence and appreciation of the prevalence and importance of ADPr modification of nucleic acids (8Musheev M.U. Schomacher L. Basu A. Han D. Krebs L. Scholz C. et al.Mammalian N1-adenosine PARylation is a reversible DNA modification.Nat. Commun. 2022; 13: 6138Crossref PubMed Scopus (9) Google Scholar, 9Schuller M. Ahel I. Beyond protein modification: the rise of non-canonical ADP-ribosylation.Biochem. J. 2022; 479: 463-477Crossref PubMed Scopus (16) Google Scholar, 10Weixler L. Scharinger K. Momoh J. Luscher B. Feijs K.L.H. Zaja R. ADP-ribosylation of RNA and DNA: from in vitro characterization to in vivo function.Nucleic Acids Res. 2021; 49: 3634-3650Crossref PubMed Scopus (40) Google Scholar). This review highlights our current understanding of the human enzymes employed in ADPr modification catalysis, turnover, and signaling, with a focus on genome maintenance and poly(ADP-ribose) polymerase (PARP) enzymes. PARP inhibitors (PARPi) are important tools for understanding the biology of ADPr signaling, and several PARPi are approved for use in cancer treatments. The review also covers our current knowledge on PARPi mode of action, with a particular focus on clarifying the enigmatic process known as PARP "trapping." ADPr modifications are catalyzed by ADP-ribosyltransferase (ART) enzymes that take an ADPr group from NAD+ and attach it to macromolecules. Proteins can be modified on a variety of amino acid sidechains, including Glu, Asp, Ser, Arg, and Cys (5Luscher B. Ahel I. Altmeyer M. Ashworth A. Bai P. Chang P. et al.ADP-ribosyltransferases, an update on function and nomenclature.FEBS J. 2021; 289: 7399-7410Crossref PubMed Scopus (104) Google Scholar). Nucleic acids can receive the ADPr modification on phosphorylated termini and on nucleobases (8Musheev M.U. Schomacher L. Basu A. Han D. Krebs L. Scholz C. et al.Mammalian N1-adenosine PARylation is a reversible DNA modification.Nat. Commun. 2022; 13: 6138Crossref PubMed Scopus (9) Google Scholar, 9Schuller M. Ahel I. Beyond protein modification: the rise of non-canonical ADP-ribosylation.Biochem. J. 2022; 479: 463-477Crossref PubMed Scopus (16) Google Scholar). The ADP-ribosyltransferase diphtheria toxin-like family, containing the mammalian PARP enzymes, is defined as enzymes carrying an H-Y-[E/D/Q] signature motif in their NAD+ binding sites (5Luscher B. Ahel I. Altmeyer M. Ashworth A. Bai P. Chang P. et al.ADP-ribosyltransferases, an update on function and nomenclature.FEBS J. 2021; 289: 7399-7410Crossref PubMed Scopus (104) Google Scholar) (Fig. 1B). More specifically, their active site is composed of a "donor" site split into a nicotinamide binding pocket, in which the signature catalytic triad is located, and an adenine binding pocket (7Alemasova E.E. Lavrik O.I. Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins.Nucleic Acids Res. 2019; 47: 3811-3827Crossref PubMed Scopus (232) Google Scholar). The "donor" site effectively holds the ADPr moiety that will be attached to either a target protein/nucleic acid or a PAR chain undergoing elongation. PAR chain elongation also requires the presence of an "acceptor" site pocket that holds the ADPr moiety, already attached to its target, to which a new ADPr unit from the "donor" site is added (7Alemasova E.E. Lavrik O.I. Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins.Nucleic Acids Res. 2019; 47: 3811-3827Crossref PubMed Scopus (232) Google Scholar). As most members of the ADP-ribosyltransferase diphtheria toxin-like family do not catalyze PARylation, they also do not possess such "acceptor" sites. PARP enzymes involved in genome maintenance that can catalyze the formation of PAR chains include PARP1, PARP2, TNKS1 (PARP5a), and TNKS2 (PARP5b) (Fig. 1C). PARP3 also participates in DNA repair but catalyzes the addition of a single unit of ADPr, termed mono-ADP-ribosylation (MARylation). A later section will discuss some of the mechanisms regulating the writers and their specific roles in genome maintenance. ADPr readers are comprised of a variety of binding modules that recognize PAR or MAR without removing the modification. Many DNA repair enzymes possess such modules as they are recruited to the site of damage via PAR. Among the high-affinity binding modules are the PAR-binding motif (11Gagné J.P. Isabelle M. Lo K.S. Bourassa S. Hendzel M.J. Dawson V.L. et al.Proteome-wide identification of poly(ADP-ribose) binding proteins and poly(ADP-ribose)-associated protein complexes.Nucleic Acids Res. 2008; 36: 6959-6976Crossref PubMed Scopus (320) Google Scholar) and the PAR-binding zinc fingers (PBZs) (12Ahel I. Ahel D. Matsusaka T. Clark A.J. Pines J. Boulton S.J. et al.Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins.Nature. 2008; 451: 81-85Crossref PubMed Scopus (332) Google Scholar). For example, while p53 (a transcription activator) and XPA (a scaffolding protein involved in nucleotide excision repair) bind PAR through a conserved PAR-binding motif motif (13Reber J.M. Mangerich A. Why structure and chain length matter: on the biological significance underlying the structural heterogeneity of poly(ADP-ribose).Nucleic Acids Res. 2021; 49: 8432-8448Crossref PubMed Scopus (0) Google Scholar), the histone chaperone aprataxin and polynucleotide kinase like factor (APLF) carries two PBZ motifs (12Ahel I. Ahel D. Matsusaka T. Clark A.J. Pines J. Boulton S.J. et al.Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins.Nature. 2008; 451: 81-85Crossref PubMed Scopus (332) Google Scholar). The tandem PBZ motifs of APLF were found to recognize PARP2 branching (6Chen Q. Kassab M.A. Dantzer F. Yu X. PARP2 mediates branched poly ADP-ribosylation in response to DNA damage.Nat. Commun. 2018; 9: 3233Crossref PubMed Scopus (97) Google Scholar), although it is currently unclear how they may coordinate to mediate such binding (14Eustermann S. Brockmann C. Mehrotra P.V. Yang J.C. Loakes D. West S.C. et al.Solution structures of the two PBZ domains from human APLF and their interaction with poly(ADP-ribose).Nat. Struct. Mol. Biol. 2010; 17: 241-243Crossref PubMed Scopus (83) Google Scholar). In fact, APLF preference for PAR branches could not be reproduced in a recent study (15Löffler T. Krüger A. Zirak P. Winterhalder M.J. Müller A.L. Fischbach A. et al.Influence of chain length and branching on poly(ADP-ribose)-protein interactions.Nucleic Acids Res. 2023; 51: 536-552Crossref PubMed Scopus (2) Google Scholar). PAR branching is generally accepted to be of low abundance, which could explain the difficulty in identifying modules specifically recognizing this modification. Other PAR-binding modules include WWE domains and BRCT domains (Fig. 1D) (13Reber J.M. Mangerich A. Why structure and chain length matter: on the biological significance underlying the structural heterogeneity of poly(ADP-ribose).Nucleic Acids Res. 2021; 49: 8432-8448Crossref PubMed Scopus (0) Google Scholar). Of note, RNA- and DNA-recognition motifs, like the oligonucleotide/oligosaccharide-binding fold, can also interact with PAR as it is essentially a nucleic acid polymer chemically similar to RNA and DNA. In fact, many readers carrying such modules will shift their interaction between PAR, RNA, and DNA, depending on the PAR chain length (13Reber J.M. Mangerich A. Why structure and chain length matter: on the biological significance underlying the structural heterogeneity of poly(ADP-ribose).Nucleic Acids Res. 2021; 49: 8432-8448Crossref PubMed Scopus (0) Google Scholar). PAR readers involved in the DNA damage response (DDR) are further discussed below. Enzymes that digest or remove ADPr modifications are referred to as erasers. Notable PAR erasers during the cellular response to DNA damage include poly(ADP-ribose) glycohydrolase (PARG) and (ADP-ribosyl)hydrolase 3 (ARH3) (Fig. 1E). Many thorough reviews have recently been written about PARG, and ARH3 with a focus on structure, substrate recognition, and function (16Rack J.G.M. Liu Q. Zorzini V. Voorneveld J. Ariza A. Honarmand Ebrahimi K. et al.Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal.Nat. Commun. 2021; 12: 4581Crossref PubMed Scopus (33) Google Scholar, 17Schützenhofer K. Rack J.G.M. Ahel I. The making and breaking of serine-ADP-ribosylation in the DNA damage response.Front. Cell Dev. Biol. 2021; 9745922Crossref PubMed Scopus (8) Google Scholar). We provide a summary of their activities in this section. PARG hydrolyzes with high efficacy the ribose–ribose bonds within PAR chains. As such, PARG degrades linear and branched chains, but cannot remove the last, protein-linked moiety of ADPr, thus leaving a MARylation mark on its targets (18Hatakeyama K. Nemoto Y. Ueda K. Hayaishi O. Purification and characterization of poly(ADP-ribose) glycohydrolase. Different modes of action on large and small poly(ADP-ribose).J. Biol. Chem. 1986; 261: 14902-14911Abstract Full Text PDF PubMed Google Scholar, 19Braun S.A. Panzeter P.L. Collinge M.A. Althaus F.R. Endoglycosidic cleavage of branched polymers by poly(ADP-ribose) glycohydrolase.Eur. J. Biochem. 1994; 220: 369-375Crossref PubMed Google Scholar, 20Barkauskaite E. Brassington A. Tan E.S. Warwicker J. Dunstan M.S. Banos B. et al.Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities.Nat. Commun. 2013; 4: 2164Crossref PubMed Scopus (109) Google Scholar). Interestingly, PARG acts both as an exo-glycohydrolase (degrading PAR starting from its terminus, releasing ADPr units) (21Slade D. Dunstan M.S. Barkauskaite E. Weston R. Lafite P. Dixon N. et al.The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase.Nature. 2011; 477: 616-620Crossref PubMed Scopus (275) Google Scholar), but also has a weak endo-glycohydrolase that releases PAR fragments (longer than three ADPr units) that are subsequently degraded further by PARG itself, albeit inefficiently (20Barkauskaite E. Brassington A. Tan E.S. Warwicker J. Dunstan M.S. Banos B. et al.Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities.Nat. Commun. 2013; 4: 2164Crossref PubMed Scopus (109) Google Scholar, 22Pourfarjam Y. Kasson S. Tran L. Ho C. Lim S. Kim I.K. PARG has a robust endo-glycohydrolase activity that releases protein-free poly(ADP-ribose) chains.Biochem. Biophys. Res. Commun. 2020; 527: 818-823Crossref PubMed Scopus (13) Google Scholar). The removal of the MARylation left by PARG is catalyzed by the action of mono-ADP-ribosyl-acceptor hydrolases. ARH3 is one such hydrolase acting during the DDR that removes serine-linked ADP-ribosylation in both MAR and PAR forms (23Fontana P. Bonfiglio J.J. Palazzo L. Bartlett E. Matic I. Ahel I. Serine ADP-ribosylation reversal by the hydrolase ARH3.Elife. 2017; 6e28533Crossref Scopus (149) Google Scholar). Erasers capable of removing MARylation from Glu/Asp residues are typically macrodomains, such as MacroD1, MacroD2, and terminal ADP-ribose glycohydrolase 1 (24Barkauskaite E. Jankevicius G. Ahel I. Structures and mechanisms of enzymes employed in the synthesis and degradation of PARP-dependent protein ADP-ribosylation.Mol. Cell. 2015; 58: 935-946Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). Of note, many erasers that remove ADPr modifications on proteins can also remove this modification on nucleic acids. For example, phosphate-linked DNA and RNA MARylation can be reversed by PARG, MacroD2, terminal ADP-ribose glycohydrolase 1, and ARH3 (9Schuller M. Ahel I. Beyond protein modification: the rise of non-canonical ADP-ribosylation.Biochem. J. 2022; 479: 463-477Crossref PubMed Scopus (16) Google Scholar), and adenine-linked PARylation can be removed by PARG (8Musheev M.U. Schomacher L. Basu A. Han D. Krebs L. Scholz C. et al.Mammalian N1-adenosine PARylation is a reversible DNA modification.Nat. Commun. 2022; 13: 6138Crossref PubMed Scopus (9) Google Scholar). There is still much work to do to establish the regulatory mechanisms of PARP family enzymes. However, recent work has elucidated key aspects of how PARP1 activity is regulated through interaction with DNA strand breaks, which is the most potent stimulator of PAR production in cells. Indeed, PARP1 is the most abundant PARP enzyme and the primary PAR writer in the cell, as its catalytic output accounts for approximately 80 to 90% of the PAR produced (25D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions.Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (1612) Google Scholar). PARP1 domain architecture is comprised of six independently folded domains: three zinc fingers (Zn1, Zn2, and Zn3), a WGR (Trp-Gly-Arg) domain, a BRCT domain and a catalytic (CAT) domain. The CAT domain is composed of the helical domain (HD) and an ART domain in which the active site is located (Fig. 1B). PARP1 localizes to the nucleus where it scans intact chromatin via intrastrand transfer, also termed a monkey-bar mechanism (26Rudolph J. Mahadevan J. Dyer P. Luger K. Poly(ADP-ribose) polymerase 1 searches DNA via a 'monkey bar' mechanism.Elife. 2018; 7e37818Crossref PubMed Scopus (42) Google Scholar). PARP1 intrastrand transfer requires the cooperative action of the three zinc fingers, the WGR and the BRCT domains to move from one DNA molecule to another (26Rudolph J. Mahadevan J. Dyer P. Luger K. Poly(ADP-ribose) polymerase 1 searches DNA via a 'monkey bar' mechanism.Elife. 2018; 7e37818Crossref PubMed Scopus (42) Google Scholar, 27Rudolph J. Muthurajan U.M. Palacio M. Mahadevan J. Roberts G. Erbse A.H. et al.The BRCT domain of PARP1 binds intact DNA and mediates intrastrand transfer.Mol. Cell. 2021; 81: 4994-5006.e5Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). PARP1 scanning of intact chromatin does not trigger its catalytic activity (27Rudolph J. Muthurajan U.M. Palacio M. Mahadevan J. Roberts G. Erbse A.H. et al.The BRCT domain of PARP1 binds intact DNA and mediates intrastrand transfer.Mol. Cell. 2021; 81: 4994-5006.e5Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 28Benjamin R.C. Gill D.M. Poly(ADP-ribose) synthesis in vitro programmed by damaged DNA. A comparison of DNA molecules containing different types of strand breaks.J. Biol. Chem. 1980; 255: 10502-10508Abstract Full Text PDF PubMed Google Scholar). Rather, PARP1 is activated following the efficient organization of the zinc fingers and the WGR domain on the damage site (29Langelier M.F. Planck J.L. Roy S. Pascal J.M. Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1.Science. 2012; 336: 728-732Crossref PubMed Scopus (465) Google Scholar, 30Eustermann S. Wu W.F. Langelier M.F. Yang J.C. Easton L.E. Riccio A.A. et al.Structural basis of detection and signaling of DNA single-strand breaks by human PARP-1.Mol. Cell. 2015; 60: 742-754Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 31Rudolph J. Mahadevan J. Luger K. Probing the conformational changes associated with DNA binding to PARP1.Biochemistry. 2020; 59: 2003-2011Crossref PubMed Scopus (16) Google Scholar), which relays an activating signal to the CAT domain. This allosteric communication opens the HD, relieving its autoinhibitory action (32Dawicki-McKenna J.M. Langelier M.F. DeNizio J.E. Riccio A.A. Cao C.D. Karch K.R. et al.PARP-1 activation requires local unfolding of an autoinhibitory domain.Mol. Cell. 2015; 60: 755-768Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar), and causes the formation of an additional WGR-HD interface with a concomitant concerted rotation of the ART domain (33Rouleau-Turcotte É. Krastev D.B. Pettitt S.J. Lord C.J. Pascal J.M. Captured snapshots of PARP1 in the active state reveal the mechanics of PARP1 allostery.Mol. Cell. 2022; 82: 2939-2951.e5Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) to reveal the active site (Fig. 2). Of note, PARP1 recognition of DNA damage is not sequence-dependent and allows for PARP1 to interact with a variety of DNA lesions, such as single-strand breaks (SSBs), double-strand breaks (DSBs), and even apurinic and apyrimidinic sites in which the integrity of the backbone in preserved (29Langelier M.F. Planck J.L. Roy S. Pascal J.M. Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1.Science. 2012; 336: 728-732Crossref PubMed Scopus (465) Google Scholar, 30Eustermann S. Wu W.F. Langelier M.F. Yang J.C. Easton L.E. Riccio A.A. et al.Structural basis of detection and signaling of DNA single-strand breaks by human PARP-1.Mol. Cell. 2015; 60: 742-754Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 34Khodyreva S.N. Prasad R. Ilina E.S. Sukhanova M.V. Kutuzov M.M. Liu Y. et al.Apurinic/apyrimidinic (AP) site recognition by the 5'-dRP/AP lyase in poly(ADP-ribose) polymerase-1 (PARP-1).Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 22090-22095Crossref PubMed Scopus (0) Google Scholar). Interestingly, while the BRCT domain contributes to PARP1 scanning of intact chromatin, it does not appear to be involved in DNA damage binding (27Rudolph J. Muthurajan U.M. Palacio M. Mahadevan J. Roberts G. Erbse A.H. et al.The BRCT domain of PARP1 binds intact DNA and mediates intrastrand transfer.Mol. Cell. 2021; 81: 4994-5006.e5Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). On its own, catalytically active PARP1 primarily modifies aspartate and glutamate residues in the so-called "automodification region" comprised of the BRCT fold and a nearby linker region (35Ayyappan V. Wat R. Barber C. Vivelo C.A. Gauch K. Visanpattanasin P. et al.ADPriboDB 2.0: an updated database of ADP-ribosylated proteins.Nucleic Acids Res. 2021; 49: D261-D265Crossref PubMed Scopus (5) Google Scholar). PARP1 also modifies in trans other target proteins. During the DDR, PARP1 undergoes a change of specificity as it collaborates with its cofactor histone PARylation factor 1 (HPF1) to modify serine residues on histones and itself (36Bonfiglio J.J. Fontana P. Zhang Q. Colby T. Gibbs-Seymour I. Atanassov I. et al.Serine ADP-ribosylation depends on HPF1.Mol. Cell. 2017; 65: 932-940.e6Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar). The newfound ability of PARP1 to modify Ser residues is due to the formation of a joint active site with HPF1, an interaction greatly favored by HD opening, in which HPF1 inserts a Glu residue in the catalytic pocket to deprotonate the acceptor Ser and initiate the ADP-ribosylation reaction (37Suskiewicz M.J. Zobel F. Ogden T.E.H. Fontana P. Ariza A. Yang J.C. et al.HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation.Nature. 2020; 579: 598-602Crossref PubMed Scopus (139) Google Scholar, 38Sun F.H. Zhao P. Zhang N. Kong L.L. Wong C.C.L. Yun C.H. HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones.Nat. Commun. 2021; 12: 1028Crossref PubMed Scopus (38) Google Scholar) (Fig. 1B). HPF1, being much less abundant than PARP1 in the cell, relies on a "hit and run" mechanism to form the joint active site at substochiometric ratios (39Langelier M.F. Billur R. Sverzhinsky A. Black B.E. Pascal J.M. HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications.Nat. Commun. 2021; 12: 6675Crossref PubMed Scopus (27) Google Scholar). Despite this short-lived interaction, HPF1 speeds up initial Ser modification events (39Langelier M.F. Billur R. Sverzhinsky A. Black B.E. Pascal J.M. HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications.Nat. Commun. 2021; 12: 6675Crossref PubMed Scopus (27) Google Scholar) and reduces PAR elongation as it sterically blocks the acceptor site (37Suskiewicz M.J. Zobel F. Ogden T.E.H. Fontana P. Ariza A. Yang J.C. et al.HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation.Nature. 2020; 579: 598-602Crossref PubMed Scopus (139) Google Scholar). As such, Ser-linked PAR appears much shorter than Glu/Asp-linked PAR (39Langelier M.F. Billur R. Sverzhinsky A. Black B.E. Pascal J.M. HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications.Nat. Commun. 2021; 12: 6675Crossref PubMed Scopus (27) Google Scholar). Finally, HPF1 modulates PARP1 catalytic output by shifting the Ser-ADP-ribosylation balance toward histone modification relative to PARP1 automodification (39Langelier M.F. Billur R. Sverzhinsky A. Black B.E. Pascal J.M. HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications.Nat. Commun. 2021; 12: 6675Crossref PubMed Scopus (27) Google Scholar, 40Gibbs-Seymour I. Fontana P. Rack J.G.M. Ahel I. HPF1/C4orf27 is a PARP-1-interacting protein that regulates PARP-1 ADP-ribosylation activity.Mol. Cell. 2016; 62: 432-442Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar), ultimately making Ser modification the most abundant modification during the DDR (41Palazzo L. Leidecker O. Prokhorova E. Dauben H. Matic I. Ahel I. Serine is the major residue for ADP-ribosylation upon DNA damage.Elife. 2018; 7e34334Crossref PubMed Scopus (63) Google Scholar). Overall, this local burst in PAR initiates the DDR and recruits DNA repair factors that bind PAR (i.e., readers). While PARP1 is steered toward histone modification in the presence of HPF1, it still automodifies itself on a triad of serine residues, namely S499, S507, and S519 (42Prokhorova E. Zobel F. Smith R. Zentout S. Gibbs-Seymour I. Schutzenhofer K. et al.Serine-linked PARP1 auto-modification controls PARP inhibitor response.Nat. Commun. 2021; 12: 4055Crossref PubMed Scopus (44) Google Scholar). Mutating these serine residues was shown to retain PARP1 longer on DNA damage (42Prokhorova E. Zobel F. Smith R. Zentout S. Gibbs-Seymour I. Schutzenhofer K. et al.Serine-linked PARP1 auto-modification controls PARP inhibitor response.Nat. Commun. 2021; 12: 4055Crossref PubMed Scopus (44) Google Scholar), suggesting that automodification is likely needed to trigger PARP1 timely release from damage during the repair process. PARylation being a highly negatively charged PTM, charge repulsion with nearby chromatin appears to be the driving force of the release (43Murai J. Huang S.Y. Das B.B. Renaud A. Zhang Y. Doroshow J.H. et al.Trapping of PARP1 and PARP2 by clinical PARP inhibitors.Cancer Res. 2012; 72: 5588-5599Crossref PubMed Scopus (1497) Google Scholar, 44Murai J. Huang S.Y. Renaud A. Zhang Y. Ji J. Takeda S. et al.Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib.Mol. Cancer Ther. 2014; 13: 433-443Crossref PubMed Scopus (565) Google Scholar), although other mechanisms of enacting PARP1 release are still possible. Another well-studied member of the PARP family that is activated by DNA damage is PARP2, the closest homolog of PARP1 (Fig. 1C). In contrast to PARP1, PARP2 only has a short, unstructured N-terminal region (NTR) and a WGR domain to accompany its CAT domain (45Riccio A.A. Cingolani G. Pascal J.M. PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DNA damage.Nucleic Acids Res. 2016; 44: 1691-1702Crossref PubMed Google Scholar). Also, unlike PARP1, it is currently unclear how PARP2 navigates intact chromatin. However, PARP2 can be recruited to DNA damage via two mechanisms. PARP2 can either be recruited by binding the damage itself, an interaction mostly mediated by its WGR domain (45Riccio A.A. Cingolani G. Pascal J.M. PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DNA damage.Nucleic Acids Res. 2016; 44: 1691-1702Crossref PubMed Google Scholar) that has specificity for 5′ phosphorylated DNA breaks (46Langelier M.F. Riccio A.A. Pascal J.M. PARP-2 and PARP-3 are selective
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Single-strand breaks are the commonest lesions arising in cells, and defects in their repair are implicated in neurodegenerative disease. One of the earliest events during single-strand break repair (SSBR) is the rapid synthesis of poly(ADP-ribose) (PAR) by poly(ADP-ribose) polymerase (PARP), followed by its rapid degradation by poly(ADP-ribose) glycohydrolase (PARG). While the synthesis of poly(ADP-ribose) is important for rapid rates of chromosomal SSBR, the relative importance of poly(ADP-ribose) polymerase 1 (PARP-1) and PARP-2 and of the subsequent degradation of PAR by PARG is unclear. Here we have quantified SSBR rates in human A549 cells depleted of PARP-1, PARP-2, and PARG, both separately and in combination. We report that whereas PARP-1 is critical for rapid global rates of SSBR in human A549 cells, depletion of PARP-2 has only a minor impact, even in the presence of depleted levels of PARP-1. Moreover, we identify PARG as a novel and critical component of SSBR that accelerates this process in concert with PARP-1.
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Therapeutic drugs that block DNA repair, including poly (ADP-ribose) polymerase (PARP) inhibitors fail because of a lack of tumor-selectivity. When PARP inhibitors and NQO1 bioactivatable drugs (s-lapachone or isobutyldeoxynyboquinone (IB-DNQ)) are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung (NSCLC), pancreatic or breast cancers, the cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with NQO1 bioactivatable monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and NQO1 bioactivatable drugs. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy. Poly(ADP-ribose) polymerase-1 (PARP1) is crucial to multiple DNA repair pathways, including DNA base excision (BER), single strand (SSB) and double strand break (DSB) repair.
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Inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) and tankyrases are promising agents in therapeutics development for several cancers and ischemia, and common tools in studying DNA repair and signaling pathways. Ten human PARP family enzymes and seven widely used PARP inhibitors were studied using enzymatic assays and X-ray crystallography. PARP inhibitors are generally profiled in vitro using PARP catalytic domain fragments. Meanwhile, PARP enzymes are multidomain proteins and we show that full length PARP1 enzyme, and several of its closest isoforms, catalyze poly-ADP-ribosylation up to 200-fold more efficiently than their catalytic fragments do. Further, we find that using only catalytic domain fragments instead of full length PARP1 and -2 enzymes leads to misinterpretation of IC50 values by a factor of ~10. Veliparib is the most selective PARP1/2 inhibitor of five clinical PARP inhibitors. PJ34 and Rucaparib are the broadest PARP inhibitors of the seven compounds. The reportedly selective tankyrase inhibitor XAV939, known for its effects on the Wnt pathway, inhibits PARP1 and -2 with nanomolar IC50 values. Crystal structures of these inhibitors in complex with various PARP family members illustrate the molecular basis for broad vs. selective PARP inhibition. Our PARP inhibitor profile provides important guidelines both for future experimental design and for re-interpretation of previously obtained results.
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The Poly (ADP-ribose) polymerase (PARP) family has many vital capabilities in cellular processes, together with the law of transcription, apoptosis, and the DNA damage reaction. PARP1 possesses Poly (ADP-ribose) pastime and whilst activated via DNA harm, adds branched PAR chains to facilitate the recruitment of different restore proteins to promote the restore of DNA unmarried-strand breaks. PARP inhibitors (PARP1) had been the first approved cancer drugs that in particular focused the DNA damage response in BRCA1/2 mutated ovarian cancers. Considering the fact that then, there have been sizable advances in our know-how of the mechanisms in the back of sensitization of tumors to PARP inhibitors and enlargement of the use of PARP1 to treat several different most cancers types. right here, we assessment the current advances inside the proposed mechanisms of motion of PARP1, biomarkers of the tumor reaction to PARP1, clinical advances in PARP1 therapy, together with the capacity of mixture treatment plans and mechanisms of tumor resistance.
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Recent findings indicate that a major mechanism by which poly(ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they display similar capacity to inhibit PARP catalytic activity, their relative abilities to trap PARP differ by several orders of magnitude, with the ability to trap PARP closely correlating with each drug's ability to kill cancer cells. In this article, we review the available data on molecular interactions between these clinical-stage PARP inhibitors and PARP proteins, and discuss how their biologic differences might be explained by the trapping mechanism. We also discuss how to use the PARP-trapping mechanism to guide the development of PARP inhibitors as a new class of cancer therapy, both for single-agent and combination treatments.
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