BRCA Mutations: The Achilles Heel of Breast, Ovarian and Other Epithelial Cancers

Опубликована: Фев. 13, 2023

Two related tumor suppressor genes, Brca1 and Brca2, attract a lot of attention from both fundamental clinical points view. Oncogenic hereditary mutations in these genes are firmly linked to the early onset breast ovarian cancers. However, molecular mechanisms that drive extensive mutagenesis not known. In this review we hypothesize one potential behind phenomenon can be mediated by Alu mobile genomic elements. Linking BRCA1 BRCA2 general mechanism(s) genome stability DNA repair is critical ensure rationalized choice anti-cancer therapy. Accordingly, literature available on damage where proteins involved how inactivating (BRCAness) exploited We also propose hypothesis explains why epithelial tissues preferentially susceptible BRCA genes. Finally, discuss perspectives novel therapeutic approaches for treating BRCAness

Язык: Английский

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The proofreading exonuclease of leading-strand DNA polymerase epsilon prevents replication fork collapse at broken template strands

Nucleic Acids Research, Год журнала: 2023, Номер 51(22), С. 12288 - 12302

Опубликована: Ноя. 8, 2023

Abstract Leading-strand DNA replication by polymerase epsilon (Polϵ) across single-strand breaks (SSBs) causes single-ended double-strand (seDSBs), which are repaired via homology-directed repair (HDR) and suppressed fork reversal (FR). Although previous studies identified many molecules required for hydroxyurea-induced FR, FR at seDSBs is poorly understood. Here, we that specifically mediate seDSBs. Because requires poly(ADP ribose)polymerase 1 (PARP1), hypothesized seDSB/FR-associated would increase tolerance to camptothecin (CPT) but not the PARP inhibitor olaparib, even though both anti-cancer agents generate Indeed, uncovered Polϵ exonuclease CTF18, a cofactor, increased CPT olaparib. To explore potential functional interactions between exonuclease, PARP1, created exonuclease-deficient POLE1exo−/−, CTF18−/−, PARP1−/−, CTF18−/−/POLE1exo−/−, PARP1−/−/POLE1exo−/−, CTF18−/−/PARP1−/− cells. Epistasis analysis indicated CTF18 were interdependent PARP1 tolerance. Remarkably, POLE1exo−/− HDR-deficient BRCA1−/− cells exhibited similar sensitivity. Moreover, combining with mutations synergistically In conclusion, newly PARP1-CTF18-Polϵ axis HDR act independently prevent collapse Olaparib inhibits this axis, explaining pronounced cytotoxic effects of olaparib on

Язык: Английский

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Identification of barriers to implementation of precision oncology in patients with rare cancers

Cancer Science, Год журнала: 2024, Номер 115(6), С. 2023 - 2035

Опубликована: Март 27, 2024

Abstract Established treatment options for rare cancers are limited by the small number of patients. The current comprehensive genomic profiling (CGP) testing might not fully exploit opportunities precision oncology in patients with cancers. Therefore, we aimed to explore factors associated CGP utility and identify barriers implementing oncology. Patients who underwent at our institution between September 2019 June 2021 were enrolled this retrospective study. Based on their results, received molecularly targeted drugs or immune checkpoint inhibitors. Univariate multivariate analyses evaluated association patient characteristics proportion receiving drugs. Overall, 790 testing. Among them, 333 identified, whom 278 (83.5%) had actionable alterations, 127 (38.1%) druggable 25 (7.5%) genomically matched therapy. was significantly higher among those evidence levels A–D (8.7%) than without (2.9%). A potential barrier is clinical evidence. We propose that be performed have maximize real‐world practice.

Язык: Английский

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Exploration of poly (ADP‐ribose) polymerase inhibitor resistance in the treatment of BRCA1/2‐mutated cancer

Genes Chromosomes and Cancer, Год журнала: 2024, Номер 63(5)

Опубликована: Май 1, 2024

Breast cancer susceptibility 1/2 (BRCA1/2) genes play a crucial role in DNA damage repair, yet mutations these increase the to tumorigenesis. Exploiting synthetic lethality mechanism between BRCA1/2 and poly(ADP-ribose) polymerase (PARP) inhibition has led development clinical approval of PARP inhibitor (PARPi), representing milestone targeted therapy for mutant tumors. This approach paved way leveraging tumor treatment strategies. Despite initial success PARPis, resistance agents diminishes their efficacy BRCA1/2-mutant Investigations into PARPi have identified replication fork stability homologous recombination repair as key factors sensitive PARPis. Additionally, studies suggest that gaps may also confer sensitivity Moreover, emerging evidence indicates correlation cisplatin resistance, suggesting potential overlap mechanisms underlying both agents. Given findings, it is imperative explore interplay particularly context platinum resistance. Understanding impact on offer insights novel therapeutic strategies overcome enhance therapies

Язык: Английский

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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

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PARP inhibition leads to synthetic lethality with key splicing-factor mutations in myelodysplastic syndromes

British Journal of Cancer, Год журнала: 2024, Номер 131(2), С. 231 - 242

Опубликована: Май 28, 2024

Язык: Английский

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An E3 ubiquitin ligase localization screen uncovers DTX2 as a novel ADP-ribosylation-dependent regulator of DNA double-strand break repair

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(8), С. 107545 - 107545

Опубликована: Июль 9, 2024

DNA double-strand breaks (DSBs) elicit an elaborate response to signal damage and trigger repair via two major pathways: nonhomologous end-joining (NHEJ), which functions throughout the interphase, homologous recombination (HR), restricted S/G2 phases. The relies, on post-translational modifications of nuclear factors coordinate mending breaks. Ubiquitylation histones chromatin-associated regulates DSB numerous E3 ubiquitin ligases are involved in this process. Despite significant progress, our understanding ubiquitin-mediated regulation remains incomplete. Here, we have performed a localization screen identify RING/U-box genome maintenance. Our approach uncovered 7 novel that recruited microirradiation stripes, suggesting potential roles signaling repair. Among these factors, DELTEX family ligase DTX2 is rapidly mobilized lesions poly ADP-ribosylation-dependent manner. retained at DSBs its WWE conserved C-terminal domains. In cells, both domains required for optimal binding mono ADP-ribosylated proteins with WWEs playing prominent role Supporting involvement repair, depletion decreases HR efficiency moderately enhances NHEJ. Furthermore, impeded BRCA1 foci formation increased 53BP1 accumulation DSBs, fine-tuning pathway choice. Finally, sensitized cancer cells X-rays PARP inhibition susceptibilities could be rescued by reexpression. Altogether, work identifies as regulator HR-mediated Maintenance stability central cell homeostasis, organismal development, reproduction (1Panier S. Wang Schumacher B. Genome Instability somatic reproductive aging.Annu. Rev. Pathol. Mech. Dis. 2024; 19: 261-290Crossref PubMed Scopus (3) Google Scholar). Therefore, all living organisms rely complex pathways prevent, detect, signal, myriad threaten integrity their genetic material daily basis (2Ciccia A. Elledge S.J. response: making it safe play knives.Mol. Cell. 2010; 40: 179-204Abstract Full Text PDF (3307) Scholar, 3Thada V. Greenberg R.A. Unpaved roads: how navigates endogenous genotoxins.DNA Repair (Amst). 2022; 118103383Crossref (5) highly deleterious can lead rearrangements and/or rapid loss essential information if undergo division without repairing chromosomes. Two shared fix breaks: eukaryotes (HR) constrained S G2 phases cycle (4Scully R. Panday Elango Willis N.A. break repair-pathway choice mammalian cells.Nat. Mol. Cell Biol. 2019; 20: 698-714Crossref (789) While mostly error-free, NHEJ may result short indels caused activity nucleases polymerases ends (5Bétermier M. Bertrand P. Lopez B.S. Is non-homologous Really Inherently error-Prone process?.PLoS Genet. 2014; 10e1004086Crossref (239) contrast, conservative carries out recombination, ideally between sister chromatids, promote seamless (6Al-Zain A.M. Symington L.S. dark side homology-directed repair.DNA 2021; 106103181Crossref (8) subsequent enactment coordinated process requires action multiple (DDR) factors. Studies over last decades shown controlled opposing activities BRCA1/BARD1, key suppressor complex. partners RIF1, REV7, Shieldin NHEJ, while BRCA1/BARD1 complex, intervenes steps (7Bunting S.F. Callén E. Wong N. Chen H.T. Polato F. Gunn et al.53BP1 inhibits brca1-deficient blocking resection breaks.Cell. 141: 243-254Abstract (1283) 8Xie Hartlerode Stucki Odate Puget Kwok al.Distinct MDC1 repair.Mol. 2007; 28: 1045-1057Abstract (191) 9Gupta Somyajit K. Narita T. Maskey Stanlie Kremer al.DNA Network analysis Reveals shieldin inhibitor sensitivity.Cell. 2018; 173: 972-988.e23Abstract (307) 10Findlay Heath J. Luo V.M. Malina Morin Coulombe Y. al.SHLD 2/FAM 35A co-operates REV choice.EMBO 37: 1-20Crossref (0) 11Dev H. Chiang T.W.W. Lescale C. de Krijger I. Martin A.G. Pilger D. al.Shieldin promotes counters BRCA1-null 954-965Crossref (269) 12Ghezraoui Oliveira Becker J.R. Bilham Moralli Anzilotti cooperation REV7–shieldin underpins structure-specific NHEJ.Nature. 560: 122-127Crossref (207) 13Sherker Chaudhary Adam Heijink Noordermeer S.M. Fradet-Turcotte al.Two redundant ubiquitin-dependent sites.EMBO Rep. 22: 1-13Crossref 14Becker Clifford G. Bonnet Groth Wilson M.D. Chapman BARD1 reads H2A lysine 15 ubiquitination direct recombination.Nature. 596: 433-437Crossref (95) 15Dai L. Dai Han Huang al.Structural insight into BRCA1-BARD1 recruitment damaged chromatin.Mol. 81: 2765-2777.e6Abstract 16Nakamura Saredi Foster B.M. Nguyen N.V. Beyer T.E. al.H4K20me0 recognition BRCA1–BARD1 directs chromatids.Nat. 21: 311-318Crossref (132) 17Densham R.M. Garvin A.J. Stone H.R. Strachan Baldock Daza-Martin al.Human counteracts chromatin barriers resection.Nat. Struct. 2016; 23: 647-655Crossref 18Hu Q. Botuyan M.V. Cui Zhao Mer Mechanisms ubiquitin-nucleosome RNF168/169 RAD18.Mol. 2017; 66: 473-487.e9Abstract (68) 19Chapman Barral Vannier J.B. Borel Steger Tomas-Loba al.RIF1 53BP1-dependent Nonhomologous end joining suppression resection.Mol. 2013; 49: 858-871Abstract (497) 20Wilson Benlekbir Sherker Julien J.P. McEwan al.The structural modified nucleosome 53BP1.Nature. 536: 100-103Crossref (181) 21Callen Di Virgilio Kruhlak M.J. Nieto-Soler mediates productive mutagenic through distinct phosphoprotein interactions.Cell. 153: 1266-1280Abstract (271) 22Di Callen Yamane Zhang W. Jankovic Gitlin A.D. al.Rif1 prevents immunoglobulin class switching.Science. 339: 711-715Crossref (332) 23Escribano-Díaz Orthwein Xing Young J.T.F. Tkáč al.A cycle-dependent regulatory circuit composed 53BP1-RIF1 BRCA1-CtIP controls choice.Mol. 872-883Abstract 24Zimmermann Lottersberger Buonomo S.B. Sfeir Lange using Rif1 control 5' resection.Science. 700-704Crossref 25Mirman Z. Takai Kibe Gong al.53BP1–RIF1–shieldin CST- Polα-dependent fill-in.Nature. 112-116Crossref (285) 26Boersma Moatti Segura-Bayona Peuscher M.H. Van Der Torre Wevers B.A. al.MAD2L2 telomeres inhibiting 5′ resection.Nature. 2015; 521: 537-540Crossref (229) 27Xu Ross Brandsma Yuan Mistrik Bouwman al.REV7 affects inhibition.Nature. 541-544Crossref (460) recruitment, exchange, activation, eventual ejection degradation heavily regulated (PTMs) include ADP-ribosylation, phosphorylation, ubiquitylation, SUMOylation (28Gupte Liu Kraus W.L. Parps adp-ribosylation: recent advances linking molecular biological outcomes.Genes Dev. 31: 101-126Crossref (482) 29Jackson S.P. Durocher Regulation responses SUMO.Mol. 795-807Abstract (491) 30Schwertman Bekker-Jensen Mailand ubiquitin-like modifiers.Nat. 17: 379-394Crossref (280) Frequent crosstalk PTMs observed, common theme being writers specific often prior substrates (31DaRosa P.A. Jiang X. Pruneda J.N. Cong Klevit R.E. al.Allosteric activation RNF146 poly(ADP-ribosyl)ation signal.Nature. 517: 223-226Crossref (160) An interesting example ADP-ribosylation (ADPr)-dependent ubiquitylation which, years, has been increasingly recognized important component DDR (32Vivelo C.A. Ayyappan Leung A.K.L. Poly(ADP-ribose)-dependent clinical implications.Biochem. Pharmacol. 167: 3-12Crossref (26) Protein ADPr induced primarily mediated ADP-ribosyl transferases PARP1, PARP2, PARP3 (33Eustermann Wu W.F. Langelier M.F. Yang J.C. Easton L.E. Riccio A.A. detection single-strand human PARP-1.Mol. 60: 742-754Abstract (227) 34Langelier Pascal J.M. PARP-1 mechanism coupling poly(ADP-ribose) synthesis.Curr. Opin. 134-143Crossref (168) Poly (ADP-ribose) (PARPs) catalyze NAD+-dependent addition poly- or mono-ADP ribose (ADPr, PARylation, MARylation) molecules onto serine, glutamate, aspartate residues target were also recently deposit nucleic acids (35Leidecker O. Bonfiglio J.J. Colby Atanassov Zaja al.Serine new residue histones.Nat. Chem. 12: 998-1000Crossref (180) 36Daniels C.M. Ong S.E. Promise proteomics study ADP-ribosylation.Mol. 58: 911-924Abstract 37Musheev M.U. Schomacher Basu Krebs Scholz al.Mammalian N1-adenosine PARylation reversible modification.Nat. Commun. 13: 6138Crossref (15) 38Weixler Feijs K.L.H. RNA TRPT1 PARPs.Nucleic Acids Res. 50: 9426-9441Crossref (21) MAR/PARylation countered glycohydrolases glycohydrolase (PARG), TARG1, ARH3 chain length duration ADP ribosylation (39Dasovich PARPs ADP-ribosylation: deciphering complexity tools.Mol. 2023; 83: 1552-1572Abstract sheer abundance PARP1 nucleus almost immediate make contributor but obstacle proper (40Caron M.C. Sharma A.K. O'Sullivan Myler L.R. Ferreira M.T. Rodrigue al.Poly(ADP-ribose) polymerase-1 antagonizes breaks.Nat. 10: 2954Crossref (117) 41Ray Chaudhuri Nussenzweig multifaceted remodelling.Nat. 18: 610-621Crossref (1036) latter situation encouraged inhibitors (PARPis) trap PARP1/2 DNA, creating efficiently kill HR-defective still debated mechanisms (42Groelly F.J. Fawkes Dagg Blackford A.N. Tarsounas Targeting cancer.Nat. Cancer. 78-94Crossref (226) 43Konstantinopoulos Ceccaldi Shapiro G.I. D'Andrea Homologous deficiency: exploiting fundamental vulnerability ovarian cancer.Cancer Discov. 5: 1137-1154Crossref (648) 44Zimmermann Murina Reijns M.A.M. Agathanggelou Challis Tarnauskaite Ž. al.CRISPR screens genomic ribonucleotides source PARP-trapping lesions.Nature. 559: 285-289Crossref (264) 45Zandarashvili M.-F. Velagapudi U.K. Hancock M.A. Steffen J.D. Billur allosteric retention breaks.Science. 2020; 368eaax6367Crossref (190) Four different including olaparib/Lynparza approved use breast, ovarian, prostate cancers. Understanding determinants PARPi sensitivity thus endeavor (46Curtin N.J. Szabo Poly(ADP-ribose) polymerase inhibition: past, present future.Nat. Drug 711-736Crossref (297) 47Rudolph Jung Luger Inhibitors PARP: number crunching structure gazing.Proc. Natl. Acad. Sci. U. 119: 1-10Crossref (51) Massive proposed relax chromatin, tether ADPr-reading more regulate architecture DNA-PARP1 condensates during (48Chappidi Quail Doll Vogel L.T. Aleksandrov Felekyan al.PARP1-DNA co-condensation drives site assembly prevent disjunction broken ends.Cell. 187: 945-961.e18Abstract (11) 49Sang C.C. Moore Tereshchenko Nosella M.L. Alderson T.R. al.PARP1 differentially partition enhance ligation.bioRxiv. ([preprint])https://doi.org/10.1101/2024.01.20.575817Crossref 50Duma Ahel function response.Biochem. Soc. Trans. 51: 995-1008Crossref Many harbor ADPr-binding specifically ubiquitylate PARylated MARylated founding member group PAR-dependent RNF146/Iduna binds PAR chains allosterically stimulated 51Wang Michaud G.A. Cheng Hinds Fan al.Recognition iso-ADP-ribose moiety suggests general (ADP-ribosyl)ation-dependent ubiquitination.Genes 2012; 26: 235-240Crossref (195) 52Kang H.C. Lee Il Shin J.H. Andrabi S.A. Chi Gagné al.Iduna (PAR)-dependent damage.Proc. 2011; 108: 14103-14108Crossref (201) 53Zhou Z.D. Chan C.H.S. Xiao Z.C. Tan E.K. Ring finger protein 146/Iduna polymer PARsylation dependent ligase.Cell Adh.. Migr. 463-471Crossref other possess HECT-type E3s TRIP12 HUWE1 demonstrated RING members DTX1, DTX2, DTX4 (54Aravind domain: interaction module ribosylation.Trends Biochem. 2001; 273-275Abstract (188) 55Gatti Imhof Baudis Altmeyer Limits trapping Constrains efficiency.Cell 32107985Abstract 56Parsons J.L. Tait P.S. Finch Dianova I.I. Edelmann Khoronenkova S.V. al.Ubiquitin ARF-BP1/Mule modulates base excision repair.EMBO 2009; 3207-3215Crossref (113) Recent analyses suggested bind vivo whether maintenance not yet investigated (57Ahmed Buetow Gabrielsen Lilla Chatrin Sibbet G.J. al.DELTEX2 domain recognizes recruits ubiquitination.Sci. Adv. 6: 629-650Crossref (29) We identified seven determined four them, accumulate PARP-dependent find tandem additional contribution from characteristic impedes agreement findings, DTX2-depleted sensitive X-ray irradiation inhibition, formally demonstrating functional relevance tolerance genotoxic stress. To uncover DDR, surveyed online databases define landscape (Fig. 1A Table S1). first extracted annotated databases: (1) Human Atlas (58Thul P.J. Akesson Wiking Mahdessian Geladaki Ait Blal subcellular map proteome.Science. 356eaal3321Crossref (1769) Scholar), (2) UniProt (59Bateman O'Donovan Magrane Alpi Antunes al.UniProt: universal knowledgebase.Nucleic 45: D158-D169Crossref (3463) LocDB (60Rastogi Rost LocDB: experimental annotations homo sapiens arabidopsis thaliana.Nucleic 39: 230-234Crossref Scholar) (4) Gene Ontology (61Ashburner Ball Blake J.A. Botstein Butler Cherry al.Gene ontology: tool unification biology. Consortium.Nat. 2000; 25: 25-29Crossref (30765) These putative proteomes compared combination exhaustive lists predicted (62Li Bengtson Ulbrich Matsuda Reddy V.A. Orth al.Genome-wide annotation MULAN, mitochondrial organelle's dynamics signaling.PLoS One. 2008; 3e1487Google 63Gao Guo al.UUCD: family-based database conjugation.Nucleic 41: 445-451Crossref included likely nuclear. interrogated high quality mass spectrometry Xenopus laevis (64Wühr Güttler Peshkin McAlister G.C. Sonnett Ishihara proteome vertebrate.Curr. 2663-2671Abstract (99) 65Itzhak D.N. Tyanova Cox Borner G.H.H. Global, quantitative dynamic mapping localization.Elife. 1-36Crossref (389) took advantage large-scale effort antibodies. Proteins immunofluorescence (IF) validated antibodies types examined 332 ligases, 106 considered (Table Of number, 37 already had strong evidence supporting 12 unavailable full-length complementary DNAs (cDNAs) too large successful lentiviral packaging 1, B F Tables S1 S3). Coding sequences remaining 57 cloned expression vectors frame FLAG hemagglutinin (HA) epitope tags individually transduced U-2 OS 1C). Microirradiation was then preferentially induce (66Gaudreau-Lapierre Garneau Djerir Marechal Investigation 405 Nm laser micro-irradiation.J. Vis. Exp. : 57410https://doi.org/10.3791/57410Crossref RNF8 PRP19, respectively after induction slowly replication A (RPA)-ssDNA occurs used positive D E) (67Kolas N.K. Nakada Ylanko Chahwan Sweeney F.D. al.Orchestration DNA-damage ligase.Science. 318: 1637-1640Crossref (738) 68Maréchal Li J.-M. Ji X.Y. C.-S. Yazinski S.a. H.D. al.PRP19 transforms sensor RPA-ssDNA ATR circuitry.Mol. 53: 235-246Abstract (194) 69Dubois Yates Gaudreau-Lapierre Clément Cappadocia Gaudreau phosphorylation-and-ubiquitylation circuitry driving recombination.Nucleic 8859-8872Crossref 70Mailand Faustrup Melander Bartek Lukas al.RNF8 ubiquitylates proteins.Cell. 131: 887-900Abstract (956) 71Wan PSO4 associates (RPA) ataxia telangiectasia-mutated Rad3-related (ATR).J. 289: 6619-6626Abstract (50) Phosphorylated H2A.X (γ-H2A.X) RPA 32 kDa subunit (RPA32) colabeling markers early (5 min) late (60 180 time points, E). Out tested candidates, 50 well-expressed did form detectable stripes. formed clear stripes microirradiated nuclei: DTX3, PCGF6, PHF21A, ZNF48, RNF34, RNF114 (Figs. 1F, S1, A–C chose concentrate characterization efforts protein, most profound striking among candidates 2, A–C).Figure 2DTX2 localizes A, schematic representation 2 isoforms immunoblot total extracts. region corresponding exon 4 presented red absent DTX2B. C, DTX2A/B lentiviruses encoding HA-tagged DTX2A/B. Subsequently, 48 h post selection, microirradiated, IF staining achieved HA γ-H2A.X RPA32 (60/180 markers. Quantification tracks. Data represent mean % DTX2A/B/γ-H2A.X RPA32-colocalizing ± SD (n = 3 replicates). E, kinetics points (min) replicates) (antibody validation Fig. S2, A–C). G, abrogates damage. Cells treated vehicle (DMSO) 5 μM (AZD-2281, olaparib) 30 min performing (B). endo DTX2/γ-H2A.X colocalizing Statistical significance established unpaired t test (p < 0.0001 (∗∗∗∗)). H I influence transfected siRNAs targeting PARG, PARP2 later, performed. bar graphs, each data point represents independent replicate. scale 10 μm. IF, immunofluorescence; glycohydrolase; DMSO, dimeth

Язык: Английский

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PARP10 promotes the repair of nascent strand DNA gaps through RAD18 mediated translesion synthesis

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

Опубликована: Июль 23, 2024

Abstract Replication stress compromises genomic integrity. Fork blocking lesions such as those induced by cisplatin and other chemotherapeutic agents arrest replication forks. Repriming downstream of these represents an important mechanism restart, however the single stranded DNA (ssDNA) gaps left behind, unless efficiently filled, can serve entry point for nucleases. Nascent strand be repaired BRCA-mediated homology repair. Alternatively, also filled translesion synthesis (TLS) polymerases. How events are regulated is still not clear. Here, we show that PARP10, a poorly-characterized mono-ADP-ribosyltransferase, recruited to nascent promote their PARP10 interacts with ubiquitin ligase RAD18 recruits it structures, resulting in ubiquitination factor PCNA. PCNA ubiquitination, turn, TLS polymerase REV1 gap filling. We recruitment subsequent REV1-mediated filling requires both catalytic activity its ability interact moreover hyperactive BRCA-deficient cells, inactivation potentiates accumulations cytotoxicity cells. Our work uncovers regulator ssDNA filling, which promotes stability

Язык: Английский

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Poly (ADP-ribose) polymerase inhibitor therapy and mechanisms of resistance in epithelial ovarian cancer

Frontiers in Oncology, Год журнала: 2024, Номер 14

Опубликована: Июль 29, 2024

Advanced epithelial ovarian cancer is the commonest cause of gynaecological deaths. First-line treatment for advanced disease includes a combination platinum-taxane chemotherapy (post-operatively or peri-operatively) and maximal debulking surgery whenever feasible. Initial response rate to high (up 80%) but most patients will develop recurrence (approximately 70-90%) succumb disease. Recently, poly-ADP-ribose polymerase (PARP) inhibition (by drugs such as Olaparib, Niraparib Rucaparib) directed synthetic lethality approach in

Язык: Английский

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Poly‐ADP‐ribosylation dynamics, signaling, and analysis

Environmental and Molecular Mutagenesis, Год журнала: 2024, Номер unknown

Опубликована: Сен. 2, 2024

ADP-ribosylation is a reversible post-translational modification that plays role as signaling mechanism in various cellular processes. This characterized by its structural diversity, highly dynamic nature, and short half-life. Hence, it tightly regulated at many levels factors fine-tune formation, downstream signaling, degradation together impacts outcomes. Poly-ADP-ribosylation an essential the DNA damage response mediates recruitment of repair to sites via their poly-ADP-ribose (PAR)-binding domains (PBDs). PAR readers, encoding PBDs, convey signal mediate outcomes some cases can be dictated diversity. Several PBD families have been identified, each with variable PAR-binding affinity specificity, also recognize bind distinct parts chain. PARylation has emerged attractive target for treatment specific cancer types, inhibition formation or selectively eliminate cells defects enhance radiation chemotherapy response. In this review, we summarize key players poly-ADP-ribosylation regulation highlight PBDs tools studying dynamics expanding potential treatment.

Язык: Английский

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