International Journal of Biological Macromolecules, Год журнала: 2024, Номер unknown, С. 139046 - 139046
Опубликована: Дек. 1, 2024
Язык: Английский
Biochemical Pharmacology, Год журнала: 2024, Номер 228, С. 116174 - 116174
Опубликована: Март 27, 2024
Язык: Английский
Процитировано
12
Biochemical Pharmacology, Год журнала: 2024, Номер 221, С. 116045 - 116045
Опубликована: Фев. 8, 2024
Cancer is a disease with high mortality rate characterized by uncontrolled proliferation of abnormal cells. The hallmarks cancer evidence the acquired cells characteristics that promote growth malignant tumours, including genomic instability and mutations, ability to evade cellular death capacity sustaining proliferative signalization. Poly(ADP-ribose) polymerase-1 (PARP1) protein plays key roles in regulation, namely DNA damage repair cell survival. inhibition PARP1 promotes homologous recombination deficiency, therefore, interest PARP has been rising as target for anticancer therapies. There are already some inhibitors approved Food Drug Administration (FDA), such Olaparib Niraparib. last compound presents its structure an indazole core. In fact, pyrazoles indazoles have raising due their various medicinal properties, namely, activity. Derivatives these compounds studied presented promising results. Therefore, this review aims address importance regulation role cancer. Moreover, it intends report comprehensive literature inhibitors, containing pyrazole scaffolds, published fifteen years, focusing on structure-activity relationship aspects, thus providing important insights design novel more effective inhibitors.
Язык: Английский
Процитировано
9
Molecular Cell, Год журнала: 2024, Номер 84(19), С. 3610 - 3626
Опубликована: Окт. 1, 2024
Язык: Английский
Процитировано
5
Oncology Letters, Год журнала: 2025, Номер 29(5), С. 1 - 14
Опубликована: Март 4, 2025
Breast cancer is one of the most prevalent malignant tumors worldwide, and triple‑negative breast (TNBC) presents a major therapeutic challenge due to lack effective targeted treatment options. Poly (ADP‑ribose) polymerase (PARP) plays critical role in DNA damage repair, its inhibitors have shown significant efficacy patients with TNBC exhibiting susceptibility gene (BRCA) mutations. The present review aimed analyze molecular mechanisms cell death induced by related PAR PARP, thoroughly exploring PARP regulatory pathways. Additionally, it intended highlight clinical trials outcomes currently used treatment. In particular, current delves into drug resistance, such as BRCA mutation reversion protein trapping, examines potential strategies overcome inhibitor resistance future. Ultimately, study aims offer novel perspectives research directions for further optimizing application therapy.
Язык: Английский
Процитировано
0
Chemical Physics Impact, Год журнала: 2025, Номер unknown, С. 100871 - 100871
Опубликована: Апрель 1, 2025
Язык: Английский
Процитировано
0
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
Процитировано
6
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. 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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. 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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
Процитировано
1
International Journal of Biological Macromolecules, Год журнала: 2024, Номер unknown, С. 139046 - 139046
Опубликована: Дек. 1, 2024
Язык: Английский
Процитировано
0