PARP1 roles in DNA repair and DNA replication: The basi(c)s of PARP inhibitor efficacy and resistance

Seminars in Oncology, Год журнала: 2023, Номер 51(1-2), С. 2 - 18

Опубликована: Сен. 6, 2023

Genome integrity is under constant insult from endogenous and exogenous sources. In order to cope, eukaryotic cells have evolved an elaborate network of DNA repair that can deal with diverse lesion types exhibits considerable functional redundancy. PARP1 a major sensor breaks established putative roles in number pathways within the network, including single- double-strand as well protection replication fork. Importantly, target small-molecule PARP inhibitors (PARPi), which are employed treatment homologous recombination (HR)-deficient tumors, latter particularly susceptible accumulation damage due inability efficiently highly toxic breaks. The clinical success PARPi has fostered extensive research into biology, shed light on involvement various genomic transactions. A goal field been understand relationship between catalytic inhibition trapping. specific consequences trapping stability basis for cytotoxicity remain matter debate. Finally, increasingly recognized its capacity elicit/modulate anti-tumor immunity. potential is, however, hindered by development resistance. Hence, efforts invested identifying factors promote resistance or sensitize PARPi. current review provides summary advances our understanding mechanistic nature, molecular inhibition, mechanisms give rise

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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A unified mechanism for PARP inhibitor-induced PARP1 chromatin retention at DNA damage sites in living cells

Cell Reports, Год журнала: 2024, Номер 43(5), С. 114234 - 114234

Опубликована: Май 1, 2024

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) not only suppress PARP1 catalytic activity but also prolong its association to damaged chromatin. Here, through live-cell imaging, we quantify the alterations in dynamics and elicited by seven PARPis over a wide range of concentrations deliver unified mechanism PARPi-induced chromatin retention. We find that gross retention at DNA damage sites is jointly governed inhibition allosteric trapping, albeit strictly independent manner—catalytic causes multiple unproductive binding-dissociation cycles PARP1, while trapping prolongs lesion-bound state greatly increase overall Importantly, stronger produces greater temporal shifts downstream repair events superior cytotoxicity, highlighting retention, complex precisely quantifiable characteristic PARPis, as valuable biomarker for PARPi efficacy. Our approach can be promptly repurposed interrogating properties DNA-repair-targeting compounds beyond PARPis.

Язык: Английский

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The logic of protein post‐translational modifications (PTMs): Chemistry, mechanisms and evolution of protein regulation through covalent attachments

BioEssays, Год журнала: 2024, Номер 46(3)

Опубликована: Янв. 21, 2024

Abstract Protein post‐translational modifications (PTMs) play a crucial role in all cellular functions by regulating protein activity, interactions and half‐life. Despite the enormous diversity of modifications, various PTM systems show parallels their chemical catalytic underpinnings. Here, focussing on that involve addition new elements to amino‐acid sidechains, I describe historical milestones fundamental concepts support current understanding PTMs. The survey covers selected key research programmes, including study phosphorylation as regulatory switch, ubiquitylation degradation signal histone functional code. contribution techniques for studying PTMs is also discussed. central part essay explores shared principles strategies observed across diverse systems, together with mechanisms substrate selection, reversibility erasers recognition reader domains. Similarities basic mechanism are highlighted implications final dedicated evolutionary trajectories beginning possible emergence context rivalry prokaryotic world. Together, provides unified perspective world major modifications.

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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The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(5), С. 2484 - 2484

Опубликована: Фев. 24, 2022

Human cells are exposed to numerous exogenous and endogenous insults every day. Unlike other molecules, DNA cannot be replaced by resynthesis, hence damage can have major consequences for the cell. The response contains overlapping signalling networks that repair maintain genomic integrity, aberrant responses increasingly described in neurodegenerative diseases. Furthermore, declines during aging, which is biggest risk factor these conditions. If unrepaired, accumulation of results death eliminate with defective genomes. This particularly important postmitotic neurons because they a limited capacity proliferate, thus must maintained life. Neuronal an process disorders. In addition, inability divide renders them susceptible senescence or re-entry cell cycle. field has expanded significantly recent years, many new mechanisms been various types, including neurons. Several linked damage. this review, we provide overview pathways induced relevant discuss possible involvement

Язык: Английский

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Structure and dynamics of the chromatin remodeler ALC1 bound to a PARylated nucleosome

eLife, Год журнала: 2021, Номер 10

Опубликована: Сен. 6, 2021

The chromatin remodeler ALC1 is recruited to and activated by DNA damage-induced poly(ADP-ribose) (PAR) chains deposited PARP1/PARP2/HPF1 upon detection of lesions. has emerged as a candidate drug target for cancer therapy its loss confers synthetic lethality in homologous recombination-deficient cells. However, structure-based design molecular analysis have been hindered the requirement PARylation highly heterogeneous nature this post-translational modification. Here, we reconstituted an PARylated nucleosome complex modified vitro using PARP2 HPF1. This was amenable cryo-EM structure determination without cross-linking, which enabled visualization several intermediate states from recognition tight binding activation remodeler. Functional biochemical assays with nucleosomes highlight importance nucleosomal epitopes productive remodeling suggest that preferentially slides away breaks.

Язык: Английский

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PARP enzyme de novo synthesis of protein-free poly(ADP-ribose)

Molecular Cell, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Язык: Английский

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Serine ADP-ribosylation marks nucleosomes for ALC1-dependent chromatin remodeling

eLife, Год журнала: 2021, Номер 10

Опубликована: Дек. 7, 2021

Serine ADP-ribosylation (ADPr) is a DNA damage-induced post-translational modification catalyzed by the PARP1/2:HPF1 complex. As list of substrates continues to expand, there need for technologies prepare mono- and poly-ADP-ribosylated proteins biochemical interrogation. Here, we investigate unique peptide ADPr activities PARP1 in absence presence HPF1. We then exploit these develop method that facilitates installation ADP-ribose polymers onto peptides with precise control over chain length site. Importantly, enzymatically are fully compatible protein ligation technologies. This chemoenzymatic synthesis strategy was employed assemble series full-length, ADP-ribosylated histones show at histone H2B serine 6 or H3 10 converts nucleosomes into robust chromatin remodeler ALC1. found ALC1 preferentially remodels ‘activated’ within heterogeneous mononucleosome populations asymmetrically dinucleosome substrates, nucleosome sufficient stimulate activity nuclear extracts. Our study identifies function describes new, highly modular approach explore impact site-specific poly-ADPr have on function.

Язык: Английский

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