Targeting the NRF2/KEAP1 pathway in cervical and endometrial cancers

European Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 941, P. 175503 - 175503

Published: Jan. 11, 2023

Language: Английский

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Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: Jan. 31, 2022

Loss or rearrangement of genetic information can result from incorrect responses to DNA double strand breaks (DSBs). The cellular DSBs encompass a range highly coordinated events designed detect and respond appropriately the damage, thereby preserving genomic integrity. In analogy with occurring during viral infection, we appropriate terms Immediate-Early, Early, Late describe pre-repair DSBs. A distinguishing feature Immediate-Early response is that large protein condensates form Early are resolved upon repair, termed foci, not visible. encompasses initial lesion sensing, involving poly (ADP-ribose) polymerases (PARPs), KU70/80, MRN, as well rapid repair by so-called 'fast-kinetic' canonical non-homologous end joining (cNHEJ). Initial binding PARPs KU70/80 complex appears be mutually exclusive at easily ligatable repaired efficiently fast-kinetic cNHEJ; process PARP-, ATM-, 53BP1-, Artemis-, resection-independent. However, more requiring processing, ensuing dynamic PARylation (polyADP ribosylation) many substrates may aid recruitment both MRN Complex rely response, largely defined ATM-dependent focal signalling molecules into condensates, regulated chromatin dynamics. Finally, integrates cell cycle phase, context, type DSB determine pathway choice. Critical choice p53 1 (53BP1) breast cancer associated (BRCA1). additional factors recruited throughout also impact choice, although these remain fully characterised. somehow channels high-fidelity pathway, typically either 'slow-kinetic' cNHEJ homologous recombination (HR). specific components machinery results in cells utilising remaining effect but often cost increased mutagenesis. Here discuss regulation proceeding itself.

Language: Английский

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Structural basis for APE1 processing DNA damage in the nucleosome

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Sept. 14, 2022

Abstract Genomic DNA is continually exposed to endogenous and exogenous factors that promote damage. Eukaryotic genomic packaged into nucleosomes, which present a barrier accessing effectively repairing The mechanisms by repair proteins overcome this damage in the nucleosome protect stability unknown. Here, we determine how base excision (BER) endonuclease AP-endonuclease 1 (APE1) recognizes cleaves nucleosome. Kinetic assays APE1 solvent-exposed AP sites with 3 − 6 orders of magnitude higher efficiency than occluded sites. A cryo-electron microscopy structure bound containing site reveal uses sculpting mechanism for recognition, where bends nucleosomal access site. Notably, additional biochemical structural characterization identify contacts between histone octamer prevent efficient processing APE1. These findings provide rationale position-dependent activity BER suggests ability sculpt drives chromatin.

Language: 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, 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

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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

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Zinc finger proteins: guardians of genome stability

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 25, 2024

Zinc finger proteins (ZNF), a unique yet diverse group of proteins, play pivotal roles in fundamental cellular mechanisms including transcription regulation, chromatin remodeling, protein/RNA homeostasis, and DNA repair. Consequently, the mis regulation ZNF can result variety human diseases, ranging from neurodevelopmental disorders to several cancers. Considering promising results damage repair (DDR) inhibition clinic, as therapeutic strategy for patients with homologous recombination (HR) deficiency, identifying other potential targetable DDR emerged vulnerabilities resistant tumor cells is essential, especially when considering burden acquired drug resistance. Importantly, there are growing number studies new ZNFs revealing their significance pathways, highlighting great targets DDR-inhibition therapy. Although, still many uncharacterized ZNF-containing unknown biological function. In this review, we highlight major classes observed functions mammalian cells. We briefly introduce well-known newly discovered describe molecular contributions health disease, cancer. Finally, discuss mechanisms, cancer therapy advances exploiting future disease.

Language: Английский

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Role of PARP in TNBC: Mechanism of Inhibition, Clinical Applications, and Resistance

Biomedicines, Journal Year: 2021, Volume and Issue: 9(11), P. 1512 - 1512

Published: Oct. 21, 2021

Triple-negative breast cancer is a combative type with highly inflated histological grade that leads to poor theragnostic value. Gene, protein, and receptor-specific targets have shown effective clinical outcomes in patients TNBC. Cells are frequently exposed DNA-damaging agents. DNA damage repaired by multiple pathways; accumulations of mutations occur due one or more pathways lead alterations normal cellular mechanisms, which development tumors. Advances target-specific therapies significant momentum; most treatment options cause off-target toxicity side effects on healthy tissues. PARP (poly(ADP-ribose) polymerase) major protein involved repair pathways, base excision (BER) homologous recombination (HR), nonhomologous end-joining (NEJ) deficiency-based mechanisms. deficits an increased risk tumor formation. Inhibitors favorably kill cells BRCA-mutations. For few years, PARPi has promising activity as chemotherapeutic agent BRCA1- BRCA2-associated cancers, combination chemotherapy triple-negative cancer. This review covers the current results trials testing future directions for field inhibitor development.

Language: Английский

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Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

Cancers, Journal Year: 2021, Volume and Issue: 14(1), P. 96 - 96

Published: Dec. 25, 2021

Uveal melanoma (UM) is the most common malignant intraocular tumour in adult population. It a rare cancer with an incidence of nearly five cases per million inhabitants year, which develops from uncontrolled proliferation melanocytes choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either symptoms like blurred vision photopsia, without symptoms, being detected routine eye exams. Over course disease, metastases, are dormant, develop 50% patients, preferentially liver. Despite decades intensive research, only approach proven to mildly control disease spread early treatments directed ablate liver such as surgical excision chemoembolization. However, patients have limited life expectancy once metastases detected, since there therapeutic approaches for metastatic including immunotherapy, unlike cutaneous melanoma, has been mostly ineffective UM patients. Therefore, order offer best care possible these urgent need find robust models that can accurately predict prognosis UM, well strategies effectively block and/or limit disease. Here, we summarized current knowledge about by compiling relevant epidemiological, clinical, pathological and molecular data. Then, revisited important prognostic factors currently used evaluation follow-up primary cases. Afterwards, addressed emerging biomarkers comprehensively reviewing gene signatures, immunohistochemistry-based markers proteomic resulting research studies conducted over past three years. Finally, discussed hurdles field anticipated future challenges novel avenues UM.

Language: Английский

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Human PARP1 substrates and regulators of its catalytic activity: An updated overview

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 23, 2023

Poly (ADP-ribose) polymerase 1 (PARP1) is a key DNA damage sensor that recruited to damaged sites after strand breaks initiate repair. This achieved by catalyzing attachment of ADP-ribose moieties, which are donated from NAD + , on the amino acid residues itself or other acceptor proteins. PARP inhibitors (PARPi) inhibit catalytic activity and induce trapping commonly used for treating BRCA1/2 -deficient breast ovarian cancers through synergistic lethality. Unfortunately, resistance PARPi frequently occurs. In this review, we present novel substrates regulators PARP1-catalyzed poly (ADP-ribosyl)ation (PARylatison) have been identified in last 3 years. The overall aim presentation protein interactions potential therapeutic intervention overcoming PARPi.

Language: Английский

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Biomarkers beyond BRCA: promising combinatorial treatment strategies in overcoming resistance to PARP inhibitors

Journal of Biomedical Science, Journal Year: 2022, Volume and Issue: 29(1)

Published: Oct. 25, 2022

Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) exploit the concept of synthetic lethality and offer great promise in treatment tumors with deficiencies homologous recombination (HR) repair. PARPi exert antitumor activity by blocking Poly(ADP-ribosyl)ation (PARylation) trapping PARP1 on damaged DNA. To date, U.S. Food Drug Administration (FDA) has approved four for several cancer types including ovarian, breast, pancreatic prostate cancer. Although patients HR-deficient benefit from PARPi, majority ultimately develop acquired resistance to PARPi. Furthermore, even though BRCA1/2 mutations are commonly used as markers sensitivity current clinical practice, not all have PARPi-sensitive disease. Thus, there is an urgent need elucidate molecular mechanisms support development rational effective strategies aimed at overcoming well reliable biomarkers accurately identify who will most likely either monotherapy or combination other agents, so called marker-guided therapy (Mget). In this review, we summarize driving efficacy emerging therapeutic overcome resistance. We also highlight identification potential predict guide promising PARPi-based strategies.

Language: Английский

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