Poly ADP-Ribose Signaling is Dysregulated in Huntington Disease DOI Creative Commons
Tamara Maiuri, Carlos Barba Bazan, Rachel Harding

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Ноя. 24, 2022

Abstract Huntington disease (HD) is a genetic neurodegenerative caused by CAG expansion in the Huntingtin (HTT) gene, translating to an expanded polyglutamine tract huntingtin protein. Age at onset correlates repeat length but varies decades between individuals with identical lengths. Genome-wide association studies link HD modification DNA repair and mitochondrial health pathways. Clinical show elevated damage HD, even premanifest stage. A major node influencing PARP pathway. Accumulation of poly ADP-ribose (PAR) has been implicated Alzheimer Parkinson diseases, as well cerebellar ataxia. We report that mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting Human iPSC-derived neurons patient- derived fibroblasts diminished response context damage. defined PAR-binding motif huntingtin, detected complexed PARylated proteins human cells during stress, localized mitotic chromosomes upon inhibition degradation. Direct binding was measured fluorescence polarization visualized atomic force microscopy single molecule level. While wild type mutant did not differ their ability, purified protein increased vitro PARP1 activity while not. These results provide insight into early molecular mechanism suggesting possible targets for design preventive therapies. Significance statement consensus on dysfunctional emerged research, signaling more recently implicated. In contrast, we identified deficient Huntington’s patient spinal samples cells. This may be explained inability bearing HD-causing stimulate production way does. Since drugs target degradation already developed, these findings present exciting avenue therapeutic intervention HD.

Язык: Английский

Combination strategies with PARP inhibitors in BRCA-mutated triple-negative breast cancer: overcoming resistance mechanisms DOI Creative Commons
Aditi Jain,

Alan Barge,

Christopher N. Parris

и другие.

Oncogene, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 21, 2024

Abstract Triple-negative breast cancer (TNBC) is a particularly aggressive subtype, characterised by higher incidence in younger women, rapid metastasis, and generally poor prognosis. Patients with TNBC BRCA mutations face additional therapeutic challenges due to the cancer’s intrinsic resistance conventional therapies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have emerged as promising targeted treatment for BRCA-mutated TNBC, exploiting vulnerabilities homologous recombination repair (HRR) pathway. However, despite initial success, efficacy of PARPis often compromised development mechanisms, including HRR restoration, stabilisation replication forks, reduced PARP1 trapping, drug efflux. This review explores latest breakthroughs overcoming PARPi through combination These strategies include integration chemotherapy, immunotherapy, antibody-drug conjugates, PI3K/AKT pathway inhibitors. combinations aim enhance targeting multiple progression pathways. The also discusses evolving role within broader paradigm emphasising need ongoing research clinical trials optimise strategies. By tackling associated exploring novel therapies, this sheds light on future possibilities improving outcomes patients TNBC.

Язык: Английский

Процитировано

6
Positioning Loss of PARP1 Activity as the Central Toxic Event in BRCA-Deficient Cancer DOI Creative Commons
Nathan J. MacGilvary, Sharon B. Cantor

DNA repair, Год журнала: 2024, Номер 144, С. 103775 - 103775

Опубликована: Окт. 19, 2024

The mechanisms by which poly(ADP-ribose) polymerase 1 (PARP1) inhibitors (PARPi)s inflict replication stress and/or DNA damage are potentially numerous. PARPi toxicity could derive from loss of its catalytic activity physical trapping PARP1 onto that perturbs not only function in repair and replication, but also obstructs compensating pathways. combined disruption with either the hereditary breast ovarian cancer genes, BRCA1 or BRCA2 (BRCA), results synthetic lethality. This has driven development PARP as therapies for BRCA-mutant cancers. In this review, we focus on recent findings highlight activity, rather than PARPi-induced allosteric trapping, central to efficacy BRCA deficient cells. However, review PARP-trapping is an effective strategy other genetic deficiencies. Together, conclude mechanism-of-action unilateral; enhanced differentially killing depending context. Therefore, effectively targeting cells requires intricate understanding their key underlying vulnerabilities.

Язык: Английский

Процитировано

4
In and out of Replication Stress: PCNA/RPA1-Based Dynamics of Fork Stalling and Restart in the Same Cell DOI Open Access

Teodora Dyankova-Danovska,

Sonya Uzunova,

Georgi Danovski

и другие.

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 667 - 667

Опубликована: Янв. 14, 2025

Replication forks encounter various impediments, which induce fork stalling and threaten genome stability, yet the precise dynamics of restart at single-cell level remain elusive. Herein, we devise a live-cell microscopy-based approach to follow hydroxyurea-induced subsequent 30 s resolution. We measure two distinct processes during stalling. One is rapid PCNA removal, reflects drop in DNA synthesis. The other gradual RPA1 accumulation up 2400 nt ssDNA per despite an active intra-S checkpoint. Restoring nucleotide pool enables prompt without post-replicative smooth cell cycle progression. ATR, but not ATM inhibition, accelerates nine-fold, leading exhaustion within 20 min. Fork under ATR inhibition led persistence ~600 after S-phase, reached 2500 ATR/ATM co-inhibition, with both scenarios mitotic catastrophe. MRE11 had no effect on PCNA/RPA1 regardless activity. E3 ligase RAD18 was recruited stalled replication parallel removal. Our results shed light depletion provide valuable tool for interrogating effects stress-inducing anti-cancer agents.

Язык: Английский

Процитировано

0
Cardiotoxicity induced by xanthatin via activating apoptosis and ERS pathways in zebrafish DOI

Lixin Feng,

Liyan Xu,

Jing Huang

и другие.

Drug and Chemical Toxicology, Год журнала: 2025, Номер unknown, С. 1 - 12

Опубликована: Март 24, 2025

Xanthatin, a sesquiterpene lactone compound, isolated from Chinese herb, Xanthium strumarium L, has various activities, including anti-inflammatory, anti-tumor, anti-ulcer effects. However, it been less studied in terms of its toxicity, especially the potential toxicity on heart. This study is mainly aimed to assess cardiotoxicity xanthatin vivo using zebrafish larva and vitro cardiomyocytes H9C2. The was assessed by pericardial edema, blood flow dynamics, SV-BA distance, sub-intestinal vein. apoptosis determined AO staining, red cell reduction distribution detected O-dianisidine histopathological evaluations were HE staining. anti-proliferative pro-apoptotic activities H9C2 cells EdU staining Hoechst 33342/PI double results showed that caused cardiac malformations dysfunctions, decreased heart rate, reduced count, hemodynamics, stroke volume, increased distance vein congestion. Furthermore, occurred after exposure. Additionally, cat, Mn-sod, chop, perk, hspa5 related oxidative stress ERS also changed xanthatin. Apoptotic genes caspase3 caspase9 increased. Moreover, had proapoptotic antiproliferative To sum up, these suggest stress, pathways are involved induced finding will be helpful for better understanding underlying mechanism.

Язык: Английский

Процитировано

0
Poly ADP-ribose signaling is dysregulated in Huntington disease DOI
Tamara Maiuri, Carlos Barba Bazan, Rachel Harding

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(40)

Опубликована: Сен. 27, 2024

Huntington disease (HD) is a genetic neurodegenerative caused by cytosine, adenine, guanine (CAG) expansion in the

Язык: Английский

Процитировано

3
Expanding the Perspective on PARP1 and Its Inhibitors in Cancer Therapy: From DNA Damage Repair to Immunomodulation DOI Creative Commons
Flurina Böhi, Michael O. Hottiger

Biomedicines, Год журнала: 2024, Номер 12(7), С. 1617 - 1617

Опубликована: Июль 20, 2024

The emergence of PARP inhibitors as a therapeutic strategy for tumors with high genomic instability, particularly those harboring BRCA mutations, has advanced cancer treatment. However, recent advances have illuminated multifaceted role PARP1 beyond its canonical function in DNA damage repair. This review explores the expanding roles PARP1, highlighting crucial interplay immune system during tumorigenesis. We discuss PARP1's immunomodulatory effects macrophages and T cells, particular focus on cytokine expression. Understanding these not only holds promise enhancing efficacy therapy but also paves way novel treatment regimens targeting immune-mediated inflammatory diseases.

Язык: Английский

Процитировано

2
A Comprehensive Review on PARP Inhibitors in Targeted Therapy for Cancers DOI Creative Commons

Mounika Guduri,

Samyuktha Kolluru,

Haritha Pasupulati

и другие.

Deleted Journal, Год журнала: 2024, Номер 19(2), С. 44 - 59

Опубликована: Авг. 9, 2024

The poly (ADP-ribose) polymerase (PARP) family of enzymes involves and regulates various cellular processes essential functions, such as apoptosis, transcription process, DNA repair. PARPs (PARP-1, PARP-2, PARP-3) are a branch familiar proteins that play crucial role in repairing damage human gene involved different cancers regulate the base excision repair (BER) pathway. As target-based drug therapy for cancer, inhibition PARP stops PARP-1 -2 from damaged mutated cancer cells, eventually, cells die. Considering limited available therapies treatment advanced recurrent cancers, inhibitors (PARPi) first approved drugs particularly target response to BRCA (BReast CAncer gene)-1/2 ovarian, pancreatic, prostate, breast cancers. Recently, six PARPi viz., olaparib, rucaparib, niraparib, talazoparib, fuzuloparib, pamiparib were monotherapy or combination with other classes anticancer agents maintenance Moreover, appears improve progression-free survival women platinum-sensitive ovarian an adjuvant conventional treatment. Importantly, use management germline BRCA1/2-associated is novel therapeutic strategy, representing successful targeted improving outcomes patients hereditary Although resistance these has been reported recently, however, strategies have employed overcome sensitivity breast, gastric, prostate

Язык: Английский

Процитировано

2
Talazoparib enhances resection at DSBs and renders HR-proficient cancer cells susceptible to Polθ inhibition DOI Creative Commons
Xixi Lin, Aashish Soni,

Razan Hessenow

и другие.

Radiotherapy and Oncology, Год журнала: 2024, Номер 200, С. 110475 - 110475

Опубликована: Авг. 13, 2024

The PARP inhibitor (PARPi), Talazoparib (BMN673), effectively and specifically radiosensitizes cancer cells. Radiosensitization is mediated by a shift in the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) toward PARP1-independent, alternative end-joining (alt-EJ). polymerase theta (Polθ) key component this PARP1-independent alt-EJ pathway we show here that its inhibition can further radiosensitize talazoparib-treated purpose present work to explore mechanisms dynamics underpinning enhanced talazoparib radiosensitization Polθ inhibitors HR-proficient

Язык: Английский

Процитировано

1
Regulation of PARP1/2 and the tankyrases: emerging parallels DOI Creative Commons
Matthew Jessop,

Benjamin J. Broadway,

Katy Miller

и другие.

Biochemical Journal, Год журнала: 2024, Номер 481(17), С. 1097 - 1123

Опубликована: Авг. 23, 2024

ADP-ribosylation is a prominent and versatile post-translational modification, which regulates diverse set of cellular processes. Poly-ADP-ribose (PAR) synthesised by the poly-ADP-ribosyltransferases PARP1, PARP2, tankyrase (TNKS), 2 (TNKS2), all are linked to human disease. PARP1/2 inhibitors have entered clinic target cancers with deficiencies in DNA damage repair. Conversely, continued face obstacles on their way clinical use, largely owing our limited knowledge molecular impacts effector pathways, concerns around tolerability. Whilst detailed structure-function studies revealed comprehensive picture regulation, mechanistic understanding tankyrases lags behind, thereby appreciation consequences inhibition. Despite large differences architecture contexts, recent work has striking parallels regulatory principles that govern these enzymes. This includes low basal activity, activation intra- or inter-molecular assembly, negative feedback regulation auto-PARylation, allosteric communication. Here we compare point towards emerging open questions, whose pursuit will inform future drug development efforts.

Язык: Английский

Процитировано

1
Poly ADP-Ribose Signaling is Dysregulated in Huntington Disease DOI Creative Commons
Tamara Maiuri, Carlos Barba Bazan, Rachel Harding

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Ноя. 24, 2022

Abstract Huntington disease (HD) is a genetic neurodegenerative caused by CAG expansion in the Huntingtin (HTT) gene, translating to an expanded polyglutamine tract huntingtin protein. Age at onset correlates repeat length but varies decades between individuals with identical lengths. Genome-wide association studies link HD modification DNA repair and mitochondrial health pathways. Clinical show elevated damage HD, even premanifest stage. A major node influencing PARP pathway. Accumulation of poly ADP-ribose (PAR) has been implicated Alzheimer Parkinson diseases, as well cerebellar ataxia. We report that mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting Human iPSC-derived neurons patient- derived fibroblasts diminished response context damage. defined PAR-binding motif huntingtin, detected complexed PARylated proteins human cells during stress, localized mitotic chromosomes upon inhibition degradation. Direct binding was measured fluorescence polarization visualized atomic force microscopy single molecule level. While wild type mutant did not differ their ability, purified protein increased vitro PARP1 activity while not. These results provide insight into early molecular mechanism suggesting possible targets for design preventive therapies. Significance statement consensus on dysfunctional emerged research, signaling more recently implicated. In contrast, we identified deficient Huntington’s patient spinal samples cells. This may be explained inability bearing HD-causing stimulate production way does. Since drugs target degradation already developed, these findings present exciting avenue therapeutic intervention HD.

Язык: Английский

Процитировано

1