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1. Fosfomycin, from susceptibility to resistance: Impact of the new guidelines on breakpoints

Author

Farfour, E., Degand, N., Riverain, E., Fihman, V., Le Brun, C., Péan de Ponfilly, G., Muggeo, A., Jousset, A., Piau, C., Lesprit, P., Chatelain, N., Dortet, L., Poisson, A., Guillard, T., Limelette, A., Mizrahi, A., Le Monnier, A., Fournier, D., Potron, A., Morand, P., Janvier, F., Otto, M.-P., Woerther, P.-L., Decousser, J.-W., Corvec, S., Plouzeau-Jayle, C., Broutin, L., Yin, N., Héry-Arnaud, G., Beauruelle, C., Grillon, Antoine, Lecuru, M., Bille, E., Godreuil, S., Jean Pierre, H., Jean-Pierre, Hélène, Amara, M., Henry, A., Zahar, J.-R., Carbonelle, E., Jaureguy, F., Lomont, A., Isnard, C., Cattoir, V., Canis, F., Diedrich, T., Flevin, E., Merens, A., Jacquier, H., Gyde, E., Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Besançon (CHU Besançon), Hôpital Foch [Suresnes], Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital Henri Mondor, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Universitaire de Reims (CHU Reims), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Pontchaillou [Rennes], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hopital d'instruction des armées Sainte-Anne [Toulon] (HIA), CHU Henri Mondor, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut Gustave Roussy (IGR), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Virulence bactérienne précoce : fonctions cellulaires et contrôle de l'infection aiguë et subaiguë, Université de Strasbourg (UNISTRA), CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Hydrosciences Montpellier (HSM), Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier de Versailles André Mignot (CHV), Hôpital Avicenne [AP-HP], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire [Rennes], Centre hospitalier [Valenciennes, Nord], Centre hospitalier de Dieppe, Hôpital d'Instruction des Armées Begin, and Service de Santé des Armées

Subjects
Klebsiella spp, [SDV]Life Sciences [q-bio], Microbial Sensitivity Tests, Fosfomycin, Biology, Microbiology, 03 medical and health sciences, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Enterobacterales, Drug Resistance, Bacterial, medicine, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Bacteria, 030306 microbiology, Breakpoint, Broth microdilution, Anti-Bacterial Agents, 3. Good health, Infectious Diseases, T Urinary tract infection, Practice Guidelines as Topic, EUCAS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

The fosfomycin breakpoint using the disc diffusion method (DDM) changed in the 2019 CA-SFM/EUCAST guidelines v2 (24mm versus 19mm). We assessed its impact on categorization of Enterobacterales recovered from urine samples in emergency departments. A total of 7749 and 2348 strains were tested using the DDM and the broth microdilution method (BMD), respectively. The DDM with the 19-mm breakpoint was in accordance with the BMD. Using the 24-mm breakpoint, the overall rate of fosfomycin resistance in Enterobacterales increased by three-fold (5.6% vs 18.1%, P0.01) and reached 2.8% and 86.5% in E. coli and K. pneumoniae, respectively. French guidelines for the management of community-acquired UTI remain appropriate. The accuracy of the methods for routine fosfomycin susceptibility testing should be assessed. The role of fosfomycin in the treatment of documented CA-UTI due to Enterobacterales other than E. coli should be evaluated considering its rate of resistance and recent data reporting low accuracy.

Published
2020

2. PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation

Author

John M. Pascal, Keli Agama, Lisa M. Miller Jenkins, Sourav Saha, Yves Pommier, Shar-yin N. Huang, Yilun Sun, Jiji Chen, Wenjie Wang, and Yijun P. Su

Subjects
Proteasome Endopeptidase Complex, DNA Repair, Glycoside Hydrolases, DNA repair, Science, General Physics and Astronomy, Article, General Biochemistry, Genetics and Molecular Biology, Poly ADP Ribosylation, chemistry.chemical_compound, Ubiquitin, Humans, PARG, Multidisciplinary, Proteasome, biology, Topoisomerase, Ubiquitination, DNA adducts, DNA, General Chemistry, Chromatin, Cell biology, HEK293 Cells, DNA Topoisomerases, Type I, chemistry, Proteolysis, biology.protein, DNA supercoil, DNA Damage
Abstract

Poly(ADP)-ribosylation (PARylation) regulates chromatin structure and recruits DNA repair proteins. Using single-molecule fluorescence microscopy to track topoisomerase I (TOP1) in live cells, we found that sustained PARylation blocked the repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) in a similar fashion as inhibition of the ubiquitin-proteasome system (UPS). PARylation of TOP1-DPC was readily revealed by inhibiting poly(ADP-ribose) glycohydrolase (PARG), indicating the otherwise transient and reversible PARylation of the DPCs. As the UPS is a key repair mechanism for TOP1-DPCs, we investigated the impact of TOP1-DPC PARylation on the proteasome and found that the proteasome is unable to associate with and digest PARylated TOP1-DPCs. In addition, PARylation recruits the deubiquitylating enzyme USP7 to reverse the ubiquitylation of PARylated TOP1-DPCs. Our work identifies PARG as repair factor for TOP1-DPCs by enabling the proteasomal digestion of TOP1-DPCs. It also suggests the potential regulatory role of PARylation for the repair of a broad range of DPCs., TOP1 resolves DNA supercoils by forming cleavage complexes (TOP1cc) that are trapped by TOP1 inhibitors. Here the authors provide insights into the mechanistic understanding of TOP1cc PARylation, showing that inhibition of PARG results in stabilization of TOP1cc PARylation that blocks the proteasomal degradation of TOP1cc.

Published
2021

3. Exonuclease VII repairs quinolone-induced damage by resolving DNA gyrase cleavage complexes

Author

Yuk-Ching Tse-Dinh, Yves Pommier, Arnaud Vanden Broeck, Shar-yin N. Huang, Andres Canela, Valérie Lamour, Brianna B. Mitchell, Nadim Majdalani, Stephanie A. Michaels, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Kyoto University, Florida International University [Miami] (FIU), univOAK, Archive ouverte, and Kyoto University [Kyoto]

Subjects
Exonucleases, medicine.drug_class, [SDV.CAN]Life Sciences [q-bio]/Cancer, Quinolones, Cleavage (embryo), DNA gyrase, Biochemistry, Microbiology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Research Articles, 030304 developmental biology, 0303 health sciences, Nuclease, Multidisciplinary, biology, Bacteria, 030306 microbiology, Chemistry, Topoisomerase, SciAdv r-articles, DNA, Quinolone, biology.organism_classification, Exonuclease VII, 3. Good health, DNA Gyrase, biology.protein, Nucleotide excision repair, Research Article
Abstract

Exonuclease VII excises trapped DNA gyrase and provides a new strategy to overcome resistance to quinolones., The widely used quinolone antibiotics act by trapping prokaryotic type IIA topoisomerases, resulting in irreversible topoisomerase cleavage complexes (TOPcc). Whereas the excision repair pathways of TOPcc in eukaryotes have been extensively studied, it is not known whether equivalent repair pathways for prokaryotic TOPcc exist. By combining genetic, biochemical, and molecular biology approaches, we demonstrate that exonuclease VII (ExoVII) excises quinolone-induced trapped DNA gyrase, an essential prokaryotic type IIA topoisomerase. We show that ExoVII repairs trapped type IIA TOPcc and that ExoVII displays tyrosyl nuclease activity for the tyrosyl-DNA linkage on the 5′-DNA overhangs corresponding to trapped type IIA TOPcc. ExoVII-deficient bacteria fail to remove trapped DNA gyrase, consistent with their hypersensitivity to quinolones. We also identify an ExoVII inhibitor that synergizes with the antimicrobial activity of quinolones, including in quinolone-resistant bacterial strains, further demonstrating the functional importance of ExoVII for the repair of type IIA TOPcc.

Published
2021

4. The indenoisoquinoline LMP517: a novel antitumor agent targeting both TOP1 and TOP2

Author

Laetitia Marzi, Simone Difilippantonio, Yilun Sun, Yves Pommier, Shar-yin N. Huang, and Amy James

Subjects
0301 basic medicine, Cancer Research, Lung Neoplasms, Lymphoma, Mice, Nude, ATP-binding cassette transporter, Article, Substrate Specificity, Histones, 03 medical and health sciences, Mice, Random Allocation, 0302 clinical medicine, Cell Line, Tumor, medicine, Animals, Humans, Topoisomerase II Inhibitors, Molecular Targeted Therapy, Carcinoma, Small Cell, Poultry Diseases, Etoposide, biology, Chemistry, Topoisomerase, Cell cycle, Isoquinolines, Xenograft Model Antitumor Assays, Recombinant Proteins, Neoplasm Proteins, Irinotecan, 030104 developmental biology, Histone, DNA Topoisomerases, Type II, Oncology, DNA Topoisomerases, Type I, 030220 oncology & carcinogenesis, Indans, biology.protein, Cancer research, Topotecan, Camptothecin, Female, Efflux, Topoisomerase I Inhibitors, Chickens, medicine.drug
Abstract

The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan, are FDA approved for the treatment of colorectal, ovarian, lung and breast cancers. Because of the chemical instability of camptothecins, short plasma half-life, drug efflux by the multidrug-resistance ABC transporters, and the severe diarrhea produced by irinotecan, indenoisoquinoline TOP1 inhibitors (LMP400, LMP776, and LMP744), which overcome these limitations, have been developed and are in clinical development. Further modifications of the indenoisoquinolines led to the fluoroindenoisoquinolines, one of which, LMP517, is the focus of this study. LMP517 showed better antitumor activity than its parent compound LMP744 against H82 (small cell lung cancer) xenografts. Genetic analyses in DT40 cells showed a dual TOP1 and TOP2 signature with selectivity of LMP517 for DNA repair-deficient tyrosyl DNA phosphodiesterase 2 (TDP2)- and Ku70-knockout cells. RADAR assays revealed that LMP517, and to a lesser extent LMP744, induce TOP2 cleavage complexes (TOP2cc) in addition to TOP1ccs. Histone γH2AX detection showed that, unlike classical TOP1 inhibitors, LMP517 targets cells independently of their position in the cell cycle. Our study establishes LMP517 as a dual TOP1 and TOP2 inhibitor with therapeutic potential.

Published
2020

5. TDP1 suppresses mis-joining of radiomimetic DNA double-strand breaks and cooperates with Artemis to promote optimal nonhomologous end joining

Author

Lawrence F. Povirk, Kristoffer Valerie, Ajinkya S. Kawale, Shar Yin N. Huang, Brian L. Ruis, Konstantin Akopiants, Yves Pommier, and Eric A. Hendrickson

Subjects
0301 basic medicine, DNA End-Joining Repair, Cell Survival, Genome Integrity, Repair and Replication, DNA-binding protein, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Zinostatin, Genetics, medicine, Humans, DNA Breaks, Double-Stranded, RNA, Small Interfering, Nucleic Acid Synthesis Inhibitors, Nuclease, Gene knockdown, Neocarzinostatin, biology, Cytotoxins, Phosphoric Diester Hydrolases, Nuclear Proteins, Epistasis, Genetic, DNA, Endonucleases, HCT116 Cells, Cell biology, DNA-Binding Proteins, Non-homologous end joining, enzymes and coenzymes (carbohydrates), HEK293 Cells, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, biology.protein, Tumor Suppressor p53-Binding Protein 1, TDP1, medicine.drug
Abstract

The Artemis nuclease and tyrosyl-DNA phosphodiesterase (TDP1) are each capable of resolving protruding 3′-phosphoglycolate (PG) termini of DNA double-strand breaks (DSBs). Consequently, both a knockout of Artemis and a knockout/knockdown of TDP1 rendered cells sensitive to the radiomimetic agent neocarzinostatin (NCS), which induces 3′-PG-terminated DSBs. Unexpectedly, however, a knockdown or knockout of TDP1 in Artemis-null cells did not confer any greater sensitivity than either deficiency alone, indicating a strict epistasis between TDP1 and Artemis. Moreover, a deficiency in Artemis, but not TDP1, resulted in a fraction of unrepaired DSBs, which were assessed as 53BP1 foci. Conversely, a deficiency in TDP1, but not Artemis, resulted in a dramatic increase in dicentric chromosomes following NCS treatment. An inhibitor of DNA-dependent protein kinase, a key regulator of the classical nonhomologous end joining (C-NHEJ) pathway sensitized cells to NCS, but eliminated the sensitizing effects of both TDP1 and Artemis deficiencies. These results suggest that TDP1 and Artemis perform different functions in the repair of terminally blocked DSBs by the C-NHEJ pathway, and that whereas an Artemis deficiency prevents end joining of some DSBs, a TDP1 deficiency tends to promote DSB mis-joining.

Published
2018

6. Topoisomerase II-Induced Chromosome Breakage and Translocation Is Determined by Chromosome Architecture and Transcriptional Activity

Author

Elsa Callen, Nancy Wong, Keith W. Caldecott, Shar-yin N. Huang, André Nussenzweig, Amanda Day, Jan-Michael Peters, Wen Tang, Andres Canela, Gordana Wutz, Yves Pommier, Guido Zagnoli-Vieira, and Yaakov Maman

Subjects
DNA Repair, Transcription, Genetic, DNA repair, Gene Conversion, Torsion, Mechanical, Chromosomal translocation, Article, Chromosomes, Translocation, Genetic, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Transcription (biology), Humans, Topoisomerase II Inhibitors, DNA Breaks, Double-Stranded, Poly-ADP-Ribose Binding Proteins, Molecular Biology, 030304 developmental biology, Etoposide, 0303 health sciences, Cohesin, biology, Topoisomerase, fungi, Chromosome Breakage, Cell Biology, DNA, HCT116 Cells, Cell biology, Chromatin, DNA-Binding Proteins, Kinetics, DNA Topoisomerases, Type II, chemistry, Multiprotein Complexes, biology.protein, Chromosome breakage, biological phenomena, cell phenomena, and immunity, 030217 neurology & neurosurgery
Abstract

Topoisomerase II (TOP2) relieves torsional stress by forming transient cleavage complex intermediates (TOP2ccs) that contain TOP2-linked DNA breaks (DSBs). While TOP2ccs are normally reversible, they can be "trapped" by chemotherapeutic drugs such as etoposide and subsequently converted into irreversible TOP2-linked DSBs. Here, we have quantified etoposide-induced trapping of TOP2ccs, their conversion into irreversible TOP2-linked DSBs, and their processing during DNA repair genome-wide, as a function of time. We find that while TOP2 chromatin localization and trapping is independent of transcription, it requires pre-existing binding of cohesin to DNA. In contrast, the conversion of trapped TOP2ccs to irreversible DSBs during DNA repair is accelerated 2-fold at transcribed loci relative to non-transcribed loci. This conversion is dependent on proteasomal degradation and TDP2 phosphodiesterase activity. Quantitative modeling shows that only two features of pre-existing chromatin structure-namely, cohesin binding and transcriptional activity-can be used to predict the kinetics of TOP2-induced DSBs.

Published
2019

7. The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis

Author

Simone A Baechler, Antonella Spinazzola, Stephanie A. Michaels, Salim Khiati, Valentina M. Factor, L. M. Miller Jenkins, A. Ravji, Leonard M. Neckers, I. Dalla Rosa, Shar-yin N. Huang, Carole Sourbier, Yves Pommier, Hongzhi Zhang, Jens U. Marquardt, D. Becker, Martin Lang, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Mitochondrial translation, Carcinogenesis, Nude, Type I, General Physics and Astronomy, Datasets as Topic, 02 engineering and technology, Mitochondrion, medicine.disease_cause, Mice, Liver Neoplasms, Experimental, lcsh:Science, Mice, Knockout, Multidisciplinary, Liver Neoplasms, glycolysis, 021001 nanoscience & nanotechnology, Prognosis, 3. Good health, Mitochondrial, Gene Expression Regulation, Neoplastic, mitochondria, DNA Topoisomerases, Type I, Liver, Female, 0210 nano-technology, Carcinoma, Hepatocellular, Science, Knockout, Mice, Nude, Oxidative phosphorylation, Biology, DNA, Mitochondrial, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Experimental, fibroblasts, medicine, Humans, Animals, Cell Proliferation, Cell Nucleus, Tumor microenvironment, Neoplastic, Cell growth, Topoisomerase, Gene Expression Profiling, Carcinoma, Hepatocellular, General Chemistry, DNA, HCT116 Cells, Survival Analysis, Xenograft Model Antitumor Assays, 030104 developmental biology, Gene Expression Regulation, Protein Biosynthesis, Cancer cell, Cancer research, biology.protein, Carcinogens, lcsh:Q, Energy Metabolism, DNA Topoisomerases, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and transcription. Here, we report that TOP1MT is overexpressed in cancer tissues and demonstrate that TOP1MT deficiency attenuates tumor growth in human and mouse models of colon and liver cancer. Due to their mitochondrial dysfunction, TOP1MT-KO cells become addicted to glycolysis, which limits synthetic building blocks and energy supply required for the proliferation of cancer cells in a nutrient-deprived tumor microenvironment. Mechanistically, we show that TOP1MT associates with mitoribosomal subunits, ensuring optimal mitochondrial translation and assembly of oxidative phosphorylation complexes that are critical for sustaining tumor growth. The TOP1MT genomic signature profile, based on Top1mt-KO liver cancers, is correlated with enhanced survival of hepatocellular carcinoma patients. Our results highlight the importance of TOP1MT for tumor development, providing a potential rationale to develop TOP1MT-targeted drugs as anticancer therapies., TOP1MT is a topoisomerase that is localised to mitochondria. Here, the authors show that TOP1MT has a tumor promoting role in hepatocellular carcinoma by supporting mitochondrial translation and that its deficiency limits tumorigenicity.

Published
2019

8. Parallel analysis of ribonucleotide-dependent deletions produced by yeast Top1in vitroandin vivo

Author

Jang-Eun Cho, Shar-yin N. Huang, Sue Jinks-Robertson, Peter M. J. Burgers, Stewart Shuman, and Yves Pommier

Subjects
0301 basic medicine, Saccharomyces cerevisiae Proteins, Ribonucleotide, Saccharomyces cerevisiae, Genome Integrity, Repair and Replication, Biology, Cleavage (embryo), Frameshift mutation, 03 medical and health sciences, chemistry.chemical_compound, Tandem repeat, Genetics, Frameshift Mutation, Repetitive Sequences, Nucleic Acid, Sequence Deletion, Repeat unit, Base Sequence, DNA, Ribonucleotides, biology.organism_classification, Molecular biology, 030104 developmental biology, DNA Topoisomerases, Type I, chemistry, Cytokinesis
Abstract

Ribonucleotides are the most abundant non-canonical component of yeast genomic DNA and their persistence is associated with a distinctive mutation signature characterized by deletion of a single repeat unit from a short tandem repeat. These deletion events are dependent on DNA topoisomerase I (Top1) and are initiated by Top1 incision at the relevant ribonucleotide 3'-phosphodiester. A requirement for the re-ligation activity of Top1 led us to propose a sequential cleavage model for Top1-dependent mutagenesis at ribonucleotides. Here, we test key features of this model via parallel in vitro and in vivo analyses. We find that the distance between two Top1 cleavage sites determines the deletion size and that this distance is inversely related to the deletion frequency. Following the creation of a gap by two Top1 cleavage events, the tandem repeat provides complementarity that promotes realignment to a nick and subsequent Top1-mediated ligation. Complementarity downstream of the gap promotes deletion formation more effectively than does complementarity upstream of the gap, consistent with constraints to realignment of the strand to which Top1 is covalently bound. Our data fortify sequential Top1 cleavage as the mechanism for ribonucleotide-dependent deletions and provide new insight into the component steps of this process.

Published
2016

9. Abstract LB-121: The novel ATR inhibitor M4344 and CHK1 inhibitor SRA737 overcome chemoresistance in SLFN11-negative cells in combination treatment with DNA-damaging agents

Author

Yasuhisa Murai, Yves Pommier, Ken Cheng, Junko Murai, Shar-yin N. Huang, Sirisha Chakka, Ukhyun Jo, and Lu Chen

Subjects
Cisplatin, Cancer Research, biology, Chemistry, DNA damage, Topoisomerase, Cell cycle, Oncology, DU145, PARP inhibitor, Cancer research, medicine, biology.protein, Etoposide, Camptothecin, medicine.drug
Abstract

Precision medicine is an unmet need for DNA-damaging agents with potentially severe side effects. Loss of Schlafen 11 (SLFN11) expression is frequently detected in ~50% cancer cell lines of the NCI, the Broad Institute cancer cell line panel (CCLE), and the Genomics of Drug Sensitivity in Cancer project (GDSC). Deficiency of SLFN11 expression causes chemoresistance to a broad range of DNA-damaging agents, including topoisomerase I (TOP1) inhibitors, topoisomerase II (TOP2) inhibitors, alkylating agents, DNA synthesis inhibitors and PARP inhibitors. Moreover, gene silencing of SLFN11 is observed in small cell lung cancer patient-derived xenograft models with acquired drug resistance. To identify synthetic lethal therapeutic targets to overcome chemoresistance in SLFN11 deficient cells, we performed a genome-wide RNAi screen with the human druggable genome siRNA library by using camptothecin (CPT), a TOP1 inhibitor, in SLFN11 wild-type (WT) and knock-out (KO) prostate cancer DU145 cells. Gene Ontology analysis identified the inhibition of ATR-mediated DNA repair pathway genes (ATR, CHK1, BRCA2 and RPA1) is synergistic with CPT in SLFN11 KO cells, whereas inhibition of the RNA metabolism-related genes (POLR2, PSMD3, POLR2F and PSMD11) had higher combination effects in SLFN11 WT cells. The synergistic effects by depletion of ATR-mediated DNA repair pathway in SLFN11 KO cells were validated by additional siRNAs-mediated cell viability assays. To determine whether inhibition of ATR-mediated pathway can be applied clinically, we tested the new clinical ATR (M4344) and CHK1 (SRA737) inhibitors. Treatment with non-toxic-doses of M4344 and SRA737 reversed drug resistance of the SLFN11 KO cells to TOP1 inhibitors [CPT, and clinically used topotecan and LMP400 (indotecan)]. Additionally, the same synergistic effects by combination of the ATR/CHK1inhibitors and CPT were detected in isogenic CCRF-CEM SLFN11 WT and KO leukemic lymphoblasts cells and non-isogenic DMS114 and H446 small cell lung cancer cells. We also confirmed synergy with ATR/CHK1 inhibitors in combination of other clinical DNA-damaging agents (TOP2 inhibitor: etoposide, alkylating agent: cisplatin, and PARP inhibitor: talazoparib). Molecular changes induced by the combination treatment were examined in the cell cycle by assessing DAPI and EdU incorporation, cell death with Annexin V, and DNA damage response by confocal microscopy with M4344 and CPT. Co-treatment with ATR inhibitor and CPT resulted in G2/M arrest and apoptotic cell death, and formation of micronuclei and fragmented nuclei in SLFN11 KO cells, compared with SLFN11 WT cells. Collectively, our results provide a new therapeutic rationale for the clinical development of combination treatments of chemotherapeutic DNA-targeted agents with ATR/CHK1 inhibitors based on SLFN11 status. Citation Format: Ukhyun Jo, Yasuhisa Murai, Junko Murai, Shar-yin N Huang, Sirisha Chakka, Lu Chen, Ken Cheng, Yves Pommier. The novel ATR inhibitor M4344 and CHK1 inhibitor SRA737 overcome chemoresistance in SLFN11-negative cells in combination treatment with DNA-damaging agents [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-121.

Published
2020

10. Mitochondrial tyrosyl‐ <scp>DNA</scp> phosphodiesterase 2 and its <scp>TDP</scp> 2 S short isoform

Author

Ilaria Dalla Rosa, Stephanie A. Michaels, Keli Agama, Simone A Baechler, Lisa M. Miller Jenkins, Salim Khiati, Valentina M. Factor, Yves Pommier, Shar-yin N. Huang, Sae Rin Jean, David V. Tulumello, Sudhir Varma, Junko Murai, Shana O. Kelley, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Enzymologic, 0301 basic medicine, Gene isoform, Mitochondrial DNA, DNA repair, Drug Resistance, Mitochondrion, Biochemistry, Cell Line, Gene Knockout Techniques, 03 medical and health sciences, Transcription (biology), Neoplasms, Genetics, Protein Isoforms, Humans, Molecular Biology, Tumor, biology, Chemistry, Topoisomerase, Nuclear Proteins, Cell biology, mitochondria, Alternative Splicing, Cytosol, 030104 developmental biology, Gene Expression Regulation, Doxorubicin, biology.protein, Neoplasm, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Nuclear localization sequence, Transcription Factors
Abstract

Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs abortive topoisomerase II cleavage complexes. Here, we identify a novel short isoform of TDP2 (TDP2S) expressed from an alternative transcription start site. TDP2S contains a mitochondrial targeting sequence, contributing to its enrichment in the mitochondria and cytosol, while full-length TDP2 contains a nuclear localization signal and the ubiquitin-associated domain in the N-terminus. Our study reveals that both TDP2 isoforms are present and active in the mitochondria. Comparison of isogenic wild-type (WT) and TDP2 knockout (TDP2-/-/-) DT40 cells shows that TDP2-/-/- cells are hypersensitive to mitochondrial-targeted doxorubicin (mtDox), and that complementing TDP2-/-/- cells with human TDP2 restores resistance to mtDox. Furthermore, mtDox selectively depletes mitochondrial DNA in TDP2-/-/- cells. Using CRISPR-engineered human cells expressing only the TDP2S isoform, we show that TDP2S also protects human cells against mtDox. Finally, lack of TDP2 in the mitochondria reduces the mitochondria transcription levels in two different human cell lines. In addition to identifying a novel TDP2S isoform, our report demonstrates the presence and importance of both TDP2 isoforms in the mitochondria.

Published
2018

11. Biochemical Assays for the Discovery of TDP1 Inhibitors

Author

Ganesha Rai, Rui Gao, Christophe Marchand, Wendy A. Lea, Bryan T. Mott, Andrew S. Rosenthal, Ajit Jadhav, Yves Pommier, Thomas S. Dexheimer, Andrew G. Stephen, Junko Murai, Adel Chergui, Anton Simeonov, Alena Naumova, David J. Maloney, Shar-yin N. Huang, and William L. Jorgensen

Subjects
Cancer Research, Cell Survival, Phosphodiesterase Inhibitors, DNA repair, DNA damage, Antineoplastic Agents, Article, Cell Line, law.invention, law, Animals, Humans, Gene, biology, Phosphoric Diester Hydrolases, Topoisomerase, Drug Synergism, Molecular biology, Small molecule, Peptide Fragments, Oncology, Biochemistry, Cell culture, Recombinant DNA, biology.protein, Camptothecin, Drug Screening Assays, Antitumor, Chickens, TDP1
Abstract

Drug screening against novel targets is warranted to generate biochemical probes and new therapeutic drug leads. TDP1 and TDP2 are two DNA repair enzymes that have yet to be successfully targeted. TDP1 repairs topoisomerase I–, alkylation-, and chain terminator–induced DNA damage, whereas TDP2 repairs topoisomerase II–induced DNA damage. Here, we report the quantitative high-throughput screening (qHTS) of the NIH Molecular Libraries Small Molecule Repository using recombinant human TDP1. We also developed a secondary screening method using a multiple loading gel-based assay where recombinant TDP1 is replaced by whole cell extract (WCE) from genetically engineered DT40 cells. While developing this assay, we determined the importance of buffer conditions for testing TDP1, and most notably the possible interference of phosphate-based buffers. The high specificity of endogenous TDP1 in WCE allowed the evaluation of a large number of hits with up to 600 samples analyzed per gel via multiple loadings. The increased stringency of the WCE assay eliminated a large fraction of the initial hits collected from the qHTS. Finally, inclusion of a TDP2 counter-screening assay allowed the identification of two novel series of selective TDP1 inhibitors. Mol Cancer Ther; 13(8); 2116–26. ©2014 AACR.

Published
2014

12. Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2·DNA and Top2·RNA Covalent Complexes by Tyrosyl-DNA-Phosphodiesterase 2 (TDP2)

Author

Christophe Marchand, Karin C. Nitiss, Yves Pommier, Monica Abdelmalak, R. Scott Williams, John L. Nitiss, Shar Yin N. Huang, Rui Gao, and Matthew J. Schellenberg

Subjects
Models, Molecular, Ribonucleotide, Base pair, DNA repair, viruses, DNA and Chromosomes, Protein degradation, Crystallography, X-Ray, Biochemistry, chemistry.chemical_compound, Humans, Molecular Biology, biology, Phosphoric Diester Hydrolases, Topoisomerase, virus diseases, Nuclear Proteins, RNA, DNA, Cell Biology, biochemical phenomena, metabolism, and nutrition, DNA-Binding Proteins, DNA Topoisomerases, Type II, chemistry, Proteolysis, biology.protein, DNA supercoil, Protein Binding, Transcription Factors
Abstract

Eukaryotic type II topoisomerases (Top2α and Top2β) are homodimeric enzymes; they are essential for altering DNA topology by the formation of normally transient double strand DNA cleavage. Anticancer drugs (etoposide, doxorubicin, and mitoxantrone) and also Top2 oxidation and DNA helical alterations cause potentially irreversible Top2·DNA cleavage complexes (Top2cc), leading to Top2-linked DNA breaks. Top2cc are the therapeutic mechanism for killing cancer cells. Yet Top2cc can also generate recombination, translocations, and apoptosis in normal cells. The Top2 protein-DNA covalent complexes are excised (in part) by tyrosyl-DNA-phosphodiesterase 2 (TDP2/TTRAP/EAP2/VPg unlinkase). In this study, we show that irreversible Top2cc induced in suicidal substrates are not processed by TDP2 unless they first undergo proteolytic processing or denaturation. We also demonstrate that TDP2 is most efficient when the DNA attached to the tyrosyl is in a single-stranded configuration and that TDP2 can efficiently remove a tyrosine linked to a single misincorporated ribonucleotide or to polyribonucleotides, which expands the TDP2 catalytic profile with RNA substrates. The 1.6-Å resolution crystal structure of TDP2 bound to a substrate bearing a 5'-ribonucleotide defines a mechanism through which RNA can be accommodated in the TDP2 active site, albeit in a strained conformation.

Published
2014

13. Stereospecific PARP Trapping by BMN 673 and Comparison with Olaparib and Rucaparib

Author

Joel Morris, Shunichi Takeda, Shar-yin N. Huang, Yves Pommier, Yiping Zhang, James H. Doroshow, Jiuping Ji, Junko Murai, Amelie Renaud, and Beverly A. Teicher

Subjects
Cancer Research, Indoles, Veliparib, Cell Survival, Poly ADP ribose polymerase, Immunoblotting, Fluorescence Polarization, Poly(ADP-ribose) Polymerase Inhibitors, Biology, Poly (ADP-Ribose) Polymerase Inhibitor, Article, Piperazines, Olaparib, Inhibitory Concentration 50, chemistry.chemical_compound, Adenosine Triphosphate, PARP1, Cell Line, Tumor, Temozolomide, Animals, Humans, Talazoparib, Enzyme Inhibitors, Rucaparib, Dose-Response Relationship, Drug, Molecular Structure, Cell Cycle, fungi, Drug Synergism, Stereoisomerism, DNA, Methyl Methanesulfonate, Molecular biology, Dacarbazine, Oncology, chemistry, PARP inhibitor, Phthalazines, Poly(ADP-ribose) Polymerases
Abstract

Anti-PARP drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. We recently reported that several PARP inhibitors have an additional cytotoxic mechanism by trapping PARP–DNA complexes, and that both olaparib and niraparib act as PARP poisons at pharmacologic concentrations. Therefore, we have proposed that PARP inhibitors should be evaluated based both on catalytic PARP inhibition and PARP–DNA trapping. Here, we evaluated the novel PARP inhibitor, BMN 673, and compared its effects on PARP1 and PARP2 with two other clinical PARP inhibitors, olaparib and rucaparib, using biochemical and cellular assays in genetically modified chicken DT40 and human cancer cell lines. Although BMN 673, olaparib, and rucaparib are comparable at inhibiting PARP catalytic activity, BMN 673 is ∼100-fold more potent at trapping PARP–DNA complexes and more cytotoxic as single agent than olaparib, whereas olaparib and rucaparib show similar potencies in trapping PARP–DNA complexes. The high level of resistance of PARP1/2 knockout cells to BMN 673 demonstrates the selectivity of BMN 673 for PARP1/2. Moreover, we show that BMN 673 acts by stereospecific binding to PARP1 as its enantiomer, LT674, is several orders of magnitude less efficient. BMN 673 is also approximately 100-fold more cytotoxic than olaparib and rucaparib in combination with the DNA alkylating agents methyl methane sulfonate (MMS) and temozolomide. Our study demonstrates that BMN 673 is the most potent clinical PARP inhibitor tested to date with the highest efficiency at trapping PARP–DNA complexes. Mol Cancer Ther; 13(2); 433–43. ©2013 AACR.

Published
2014

14. Topoisomerase I‐mediated cleavage at unrepaired ribonucleotides generates DNA double‐strand breaks

Author

Jessica S. Williams, Thomas A. Kunkel, Mercedes E. Arana, Yves Pommier, and Shar-yin N. Huang

Subjects
0301 basic medicine, Genome instability, Ribonucleotide, Saccharomyces cerevisiae Proteins, RNase P, Ribonucleotide excision repair, Ribonuclease H, RAD51, Saccharomyces cerevisiae, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, chemistry.chemical_compound, DNA Breaks, Double-Stranded, Molecular Biology, General Immunology and Microbiology, biology, General Neuroscience, Topoisomerase, Articles, DNA, Molecular biology, Rad52 DNA Repair and Recombination Protein, 030104 developmental biology, chemistry, DNA Topoisomerases, Type I, biology.protein, Rad51 Recombinase, Homologous recombination, Gene Deletion
Abstract

Ribonuclease activity of topoisomerase I (Top1) causes DNA nicks bearing 2',3'-cyclic phosphates at ribonucleotide sites. Here, we provide genetic and biochemical evidence that DNA double-strand breaks (DSBs) can be directly generated by Top1 at sites of genomic ribonucleotides. We show that RNase H2-deficient yeast cells displayed elevated frequency of Rad52 foci, inactivation of RNase H2 and RAD52 led to synthetic lethality, and combined loss of RNase H2 and RAD51 induced slow growth and replication stress. Importantly, these phenotypes were rescued upon additional deletion of TOP1, implicating homologous recombination for the repair of Top1-induced damage at ribonuclelotide sites. We demonstrate biochemically that irreversible DSBs are generated by subsequent Top1 cleavage on the opposite strand from the Top1-induced DNA nicks at ribonucleotide sites. Analysis of Top1-linked DNA from pull-down experiments revealed that Top1 is covalently linked to the end of DNA in RNase H2-deficient yeast cells, supporting this model. Taken together, these results define Top1 as a source of DSBs and genome instability when ribonucleotides incorporated by the replicative polymerases are not removed by RNase H2.

Published
2016

15. Roles of eukaryotic topoisomerases in transcription, replication and genomic stability

Author

Yves Pommier, Yilun Sun, John L. Nitiss, and Shar Yin N. Huang

Subjects
0301 basic medicine, DNA re-replication, DNA Replication, DNA Repair, Transcription, Genetic, DNA repair, Eukaryotic DNA replication, Article, Genomic Instability, 03 medical and health sciences, Control of chromosome duplication, Animals, Humans, Molecular Biology, Genetics, biology, Topoisomerase, DNA replication, Cell Biology, Mitochondria, 030104 developmental biology, biology.protein, DNA supercoil, Origin recognition complex, DNA Topoisomerases, DNA Damage
Abstract

Topoisomerases introduce transient DNA breaks to relax supercoiled DNA, remove catenanes and enable chromosome segregation. Human cells encode six topoisomerases (TOP1, TOP1mt, TOP2α, TOP2β, TOP3α and TOP3β), which act on a broad range of DNA and RNA substrates at the nuclear and mitochondrial genomes. Their catalytic intermediates, the topoisomerase cleavage complexes (TOPcc), are therapeutic targets of various anticancer drugs. TOPcc can also form on damaged DNA during replication and transcription, and engage specific repair pathways, such as those mediated by tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2 and by endonucleases (MRE11, XPF-ERCC1 and MUS81). Here, we review the roles of topoisomerases in mediating chromatin dynamics, transcription, replication, DNA damage repair and genomic stability, and discuss how deregulation of topoisomerases can cause neurodegenerative diseases, immune disorders and cancer.

Published
2016

16. Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Repairs DNA Damage Induced by Topoisomerases I and II and Base Alkylation in Vertebrate Cells

Author

Benu Brata Das, Shunichi Takeda, Yves Pommier, Shar Yin N. Huang, Junko Murai, and Thomas S. Dexheimer

Subjects
Alkylation, DNA Repair, DNA repair, DNA damage, Molecular Sequence Data, DNA, Single-Stranded, Biology, Biochemistry, Substrate Specificity, law.invention, chemistry.chemical_compound, Antigens, Neoplasm, law, Neoplasms, Animals, Humans, Amino Acid Sequence, Poly-ADP-Ribose Binding Proteins, Molecular Biology, Cells, Cultured, Endodeoxyribonucleases, Phosphoric Diester Hydrolases, Topoisomerase, Nuclear Proteins, Cell Biology, Tyrosyl-DNA Phosphodiesterase 1, Molecular biology, DNA-Binding Proteins, DNA Topoisomerases, Type II, DNA Topoisomerases, Type I, chemistry, Vertebrates, Recombinant DNA, biology.protein, Carrier Proteins, Chickens, DNA, TDP1, DNA Damage, Nucleotide excision repair
Abstract

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs topoisomerase I cleavage complexes (Top1cc) by hydrolyzing their 3'-phosphotyrosyl DNA bonds and repairs bleomycin-induced DNA damage by hydrolyzing 3'-phosphoglycolates. Yeast Tdp1 has also been implicated in the repair of topoisomerase II-DNA cleavage complexes (Top2cc). To determine whether vertebrate Tdp1 is involved in the repair of various DNA end-blocking lesions, we generated Tdp1 knock-out cells in chicken DT40 cells (Tdp1-/-) and Tdp1-complemented DT40 cells with human TDP1. We found that Tdp1-/- cells were not only hypersensitive to camptothecin and bleomycin but also to etoposide, methyl methanesulfonate (MMS), H(2)O(2), and ionizing radiation. We also show they were deficient in mitochondrial Tdp1 activity. In biochemical assays, recombinant human TDP1 was found to process 5'-phosphotyrosyl DNA ends when they mimic the 5'-overhangs of Top2cc. Tdp1 also processes 3'-deoxyribose phosphates generated from hydrolysis of abasic sites, which is consistent with the hypersensitivity of Tdp1-/- cells to MMS and H(2)O(2). Because recent studies established that CtIP together with BRCA1 also repairs topoisomerase-mediated DNA damage, we generated dual Tdp1-CtIP-deficient DT40 cells. Our results show that Tdp1 and CtIP act in parallel pathways for the repair of Top1cc and MMS-induced lesions but are epistatic for Top2cc. Together, our findings reveal a broad involvement of Tdp1 in DNA repair and clarify the role of human TDP1 in the repair of Top2-induced DNA damage.

Published
2012

17. Lack of mitochondrial topoisomerase I (TOP1mt) impairs liver regeneration

Author

Valentina M. Factor, Shar-yin N. Huang, Hongliang Zhang, Leonard M. Neckers, Yves Pommier, Carole Sourbier, Ilaria Dalla Rosa, Snorri S. Thorgeirsson, Simone A Baechler, Salim Khiati, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
Type I, Mitochondria, Liver, Mitochondrion, Mice, chemistry.chemical_compound, Gene Knockout Techniques, 0302 clinical medicine, Adenosine Triphosphate, Carbon Tetrachloride, Cells, Cultured, chemistry.chemical_classification, Mice, Knockout, Microscopy, 0303 health sciences, Cultured, Multidisciplinary, Blotting, Biological Sciences, Glutathione, Liver regeneration, Mitochondrial, Mitochondria, 3. Good health, medicine.anatomical_structure, Liver, DNA Topoisomerases, Type I, Embryo, 030220 oncology & carcinogenesis, Hepatocyte, Chemical and Drug Induced Liver Injury, Western, Mitochondrial DNA replication, Mitochondrial DNA, Cells, Knockout, Blotting, Western, Biology, Electron, DNA, Mitochondrial, 03 medical and health sciences, Microscopy, Electron, Transmission, medicine, Transmission, Animals, Humans, 030304 developmental biology, Cell Proliferation, Reactive oxygen species, Mammalian, Regeneration (biology), DNA, Fibroblasts, Embryo, Mammalian, HCT116 Cells, Molecular biology, Liver Regeneration, chemistry, Hepatocytes, Reactive Oxygen Species, DNA Topoisomerases, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; The liver has an exceptional replicative capacity following partial hepatectomy or chemical injuries. Cellular proliferation requires increased production of energy and essential metabolites, which critically depend on the mitochondria. To determine whether Top1mt, the vertebrate mitochondrial topoisomerase, is involved in this process, we studied liver regeneration after carbon tetrachloride (CCl4) administration. TOP1mt knockout (KO) mice showed a marked reduction in regeneration and hepatocyte proliferation. The hepatic mitochondrial DNA (mtDNA) failed to increase during recovery from CCl4 exposure. Reduced glutathione was also depleted, indicating increased reactive oxygen species (ROS). Steady-state levels of ATP, O2 consumption, mtDNA, and mitochondrial mass were also reduced in primary hepatocytes from CCl4-treated KO mice. To further test whether Top1mt acted by enabling mtDNA regeneration, we tested TOP1mt KO fibroblasts and human colon carcinoma HCT116 cells and measured mtDNA after 3-d treatment with ethidium bromide. Both types of TOP1mt knockout cells showed defective mtDNA regeneration following mtDNA depletion. Our study demonstrates that Top1mt is required for normal mtDNA homeostasis and for linking mtDNA expansion with hepatocyte proliferation.

Published
2015

18. Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)

Author

Shar-yin N. Huang, Junko Murai, Rui Gao, Benu Brata Das, Christophe Marchand, and Yves Pommier

Subjects
DNA End-Joining Repair, DNA repair, medicine.drug_class, Antineoplastic Agents, Picornaviridae, Biology, Biochemistry, Antiviral Agents, Article, XRCC1, chemistry.chemical_compound, Neoplasms, medicine, Animals, Humans, Molecular Biology, chemistry.chemical_classification, DNA ligase, Phosphoric Diester Hydrolases, Topoisomerase, Nuclear Proteins, Cell Biology, Base excision repair, Molecular biology, DNA-Binding Proteins, chemistry, DNA Topoisomerases, Type I, biology.protein, RNA, Viral, Cattle, DNA, Topoisomerase inhibitor, Signal Transduction, Transcription Factors
Abstract

TDP1 and TDP2 were discovered and named based on the fact they process 3′- and 5′-DNA ends by excising irreversible protein tyrosyl-DNA complexes involving topoisomerases I and II, respectively. Yet, both enzymes have an extended spectrum of activities. TDP1 not only excises trapped topoisomerases I (Top1 in the nucleus and Top1mt in mitochondria), but also repairs oxidative damage-induced 3′-phosphoglycolates and alkylation damage-induced DNA breaks, and excises chain terminating anticancer and antiviral nucleosides in the nucleus and mitochondria. The repair function of TDP2 is devoted to the excision of topoisomerase II- and potentially topoisomerases III-DNA adducts. TDP2 is also essential for the life cycle of picornaviruses (important human and bovine pathogens) as it unlinks VPg proteins from the 5′-end of the viral RNA genome. Moreover, TDP2 has been involved in signal transduction (under the former names of TTRAP or EAPII). The DNA repair partners of TDP1 include PARP1, XRCC1, ligase III and PNKP from the base excision repair (BER) pathway. By contrast, TDP2 repair functions are coordinated with Ku and ligase IV in the non-homologous end joining pathway (NHEJ). This article summarizes and compares the biochemistry, functions, and post-translational regulation of TDP1 and TDP2, as well as the relevance of TDP1 and TDP2 as determinants of response to anticancer agents. We discuss the rationale for developing TDP inhibitors for combinations with topoisomerase inhibitors (topotecan, irinotecan, doxorubicin, etoposide, mitoxantrone) and DNA damaging agents (temozolomide, bleomycin, cytarabine, and ionizing radiation), and as novel antiviral agents.

Published
2014

19. Mapping topoisomerase sites in mitochondrial DNA with a poisonous mitochondrial topoisomerase I (Top1mt)

Author

Keli Agama, Yves Pommier, Hongliang Zhang, Shar-yin N. Huang, Ilaria Dalla Rosa, and Salim Khiati

Subjects
Mitochondrial DNA, DNA damage, Mitochondrion, Regulatory Sequences, Nucleic Acid, DNA and Chromosomes, Biochemistry, DNA, Mitochondrial, chemistry.chemical_compound, Mice, Heavy strand, medicine, Animals, Molecular Biology, Mice, Knockout, biology, Topoisomerase, Cell Biology, Molecular biology, Mitochondria, chemistry, DNA Topoisomerases, Type I, biology.protein, DNA supercoil, Camptothecin, DNA, medicine.drug, DNA Damage
Abstract

Mitochondrial topoisomerase I (Top1mt) is a type IB topoisomerase present in vertebrates and exclusively targeted to mitochondria. Top1mt relaxes mitochondrial DNA (mtDNA) supercoiling by introducing transient cleavage complexes wherein the broken DNA strand swivels around the intact strand. Top1mt cleavage complexes (Top1mtcc) can be stabilized in vitro by camptothecin (CPT). However, CPT does not trap Top1mtcc efficiently in cells and is highly cytotoxic due to nuclear Top1 targeting. To map Top1mtcc on mtDNA in vivo and to overcome the limitations of CPT, we designed two substitutions (T546A and N550H) in Top1mt to stabilize Top1mtcc. We refer to the double-mutant enzyme as Top1mt*. Using retroviral transduction and ChIP-on-chip assays with Top1mt* in Top1mt knock-out murine embryonic fibroblasts, we demonstrate that Top1mt* forms high levels of cleavage complexes preferentially in the noncoding regulatory region of mtDNA, accumulating especially at the heavy strand replication origin OH, in the ribosomal genes (12S and 16S) and at the light strand replication origin OL. Expression of Top1mt* also caused rapid mtDNA depletion without affecting mitochondria mass, suggesting the existence of specific mitochondrial pathways for the removal of damaged mtDNA.

Published
2014

20. PARP1–TDP1 coupling for the repair of topoisomerase I–induced DNA damage

Author

Yves Pommier, Valérie Schreiber, Shar-yin N. Huang, Ishita Rehman, Denis Biard, Hemanta K. Majumder, Hongliang Zhang, Subhendu K. Das, Souvik Sengupta, Papiya Majumdar, Junko Murai, Benu Brata Das, Jean-Christophe Amé, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), National Cancer Institute, National Institutes of Health, Bethesda, Laboratoire de Génétique de la Radiosensibilité (LGR), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Molecular Pharmacology, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)

Subjects
DNA Repair, DNA repair, DNA damage, Poly ADP ribose polymerase, Genome Integrity, Repair and Replication, 03 medical and health sciences, Endonuclease, XRCC1, 0302 clinical medicine, Cell Line, Tumor, Genetics, Animals, Humans, Protein Interaction Domains and Motifs, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, Phosphoric Diester Hydrolases, Sumoylation, Epistasis, Genetic, Sciences du Vivant [q-bio]/Biotechnologies, Chromatin, Cell biology, DNA-Binding Proteins, X-ray Repair Cross Complementing Protein 1, Biochemistry, DNA Topoisomerases, Type I, 030220 oncology & carcinogenesis, biology.protein, DNA supercoil, Poly(ADP-ribose) Polymerases, Nucleotide excision repair, DNA Damage
Abstract

Poly(ADP-ribose) polymerases (PARP) attach poly(ADP-ribose) (PAR) chains to various proteins including themselves and chromatin. Topoisomerase I (Top1) regulates DNA supercoiling and is the target of camptothecin and indenoisoquinoline anticancer drugs, as it forms Top1 cleavage complexes (Top1cc) that are trapped by the drugs. Endogenous and carcinogenic DNA lesions can also trap Top1cc. Tyrosyl-DNA phosphodiesterase 1 (TDP1), a key repair enzyme for trapped Top1cc, hydrolyzes the phosphodiester bond between the DNA 3′-end and the Top1 tyrosyl moiety. Alternative repair pathways for Top1cc involve endonuclease cleavage. However, it is unknown what determines the choice between TDP1 and the endonuclease repair pathways. Here we show that PARP1 plays a critical role in this process. By generating TDP1 and PARP1 double-knockout lymphoma chicken DT40 cells, we demonstrate that TDP1 and PARP1 are epistatic for the repair of Top1cc. The N-terminal domain of TDP1 directly binds the C-terminal domain of PARP1, and TDP1 is PARylated by PARP1. PARylation stabilizes TDP1 together with SUMOylation of TDP1. TDP1 PARylation enhances its recruitment to DNA damage sites without interfering with TDP1 catalytic activity. TDP1–PARP1 complexes, in turn recruit X-ray repair cross-complementing protein 1 (XRCC1). This work identifies PARP1 as a key component driving the repair of trapped Top1cc by TDP1.

Published
2014

21. TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs

Author

Yves Pommier, Ilaria Dalla Rosa, William H. Gmeiner, Alena Naumova, Shar-yin N. Huang, Thomas S. Dexheimer, and Junko Murai

Subjects
Mitochondrial DNA, Antimetabolites, Antineoplastic, DNA Repair, DNA repair, DNA damage, Anti-HIV Agents, Acyclovir, Biology, Antiviral Agents, DNA, Mitochondrial, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Zidovudine, Mice, 0302 clinical medicine, Genetics, medicine, Animals, Cells, Cultured, 030304 developmental biology, Cell Nucleus, 0303 health sciences, Nucleoside analogue, Phosphoric Diester Hydrolases, Zalcitabine, Nucleic Acid Enzymes, DNA replication, Cytarabine, Tyrosyl-DNA Phosphodiesterase 1, Molecular biology, 3. Good health, Biochemistry, chemistry, 030220 oncology & carcinogenesis, Chickens, DNA, Gene Deletion, medicine.drug, DNA Damage
Abstract

Chain-terminating nucleoside analogs (CTNAs) that cause stalling or premature termination of DNA replication forks are widely used as anticancer and antiviral drugs. However, it is not well understood how cells repair the DNA damage induced by these drugs. Here, we reveal the importance of tyrosyl-DNA phosphodiesterase 1 (TDP1) in the repair of nuclear and mitochondrial DNA damage induced by CTNAs. On investigating the effects of four CTNAs-acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT) and zalcitabine (ddC)-we show that TDP1 is capable of removing the covalently linked corresponding CTNAs from DNA 3'-ends. We also show that Tdp1-/- cells are hypersensitive and accumulate more DNA damage when treated with ACV and Ara-C, implicating TDP1 in repairing CTNA-induced DNA damage. As AZT and ddC are known to cause mitochondrial dysfunction, we examined whether TDP1 repairs the mitochondrial DNA damage they induced. We find that AZT and ddC treatment leads to greater depletion of mitochondrial DNA in Tdp1-/- cells. Thus, TDP1 seems to be critical for repairing nuclear and mitochondrial DNA damage caused by CTNAs.

Published
2013

22. Tyrosyl-DNA Phosdiesterase 1 (Tdp1) Inhibitors

Author

Christophe Marchand, Yves Pommier, and Shar-yin N. Huang

Subjects
Models, Molecular, DNA repair, Phosphodiesterase Inhibitors, Biology, Article, Patents as Topic, chemistry.chemical_compound, DNA Adducts, Biomimetics, Drug Discovery, medicine, Animals, Humans, Topoisomerase II Inhibitors, Etoposide, Pharmacology, Phosphoric Diester Hydrolases, Topoisomerase, Phosphodiesterase, Combination chemotherapy, General Medicine, Tyrosyl-DNA Phosphodiesterase 1, Benzamidines, chemistry, Biochemistry, Tetracyclines, biology.protein, Topoisomerase I Inhibitors, Ribosomes, TDP1, DNA, medicine.drug
Abstract

Inhibitors of topoisomerase I (Top1) that result in stalled Top1 cleavage complexes (Top1cc) are commonly employed against cancer. Combination chemotherapy with DNA repair inhibitors can potentially improve response to these widely used chemotherapeutics. One line of inquiry focuses on inhibitors of tyrosyl-DNA phosphodiesterase 1 (Tdp1), a repair enzyme for Top1cc. Tdp1 catalyzes the hydrolysis of DNA adducts covalently linked to the 3′-phosphate of DNA, including Top1-derived peptides and also 3′-phosphoglycolates. Tdp1 inhibitors should synergize not only with Top1-targeting drugs (camptothecins, indenoisoquinolines), but also with bleomycin, topoisomerase II (Top2) inhibitors (etoposide, doxorubicin) and DNA alkylating agents. Here, we summarize the structural-activity relationship obtained from the reported Tdp1 inhibitors. Better understanding of Top1cc repair in vivo coupled with detailed structural studies on Tdp1-inhibitor interaction will be crucial in guiding the rational design of Tdp1 inhibitors.

Published
2011

23. Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I

Author

Thomas A. Kunkel, Jang Eun Cho, Nayun Kim, Yue C. Li, Jessica S. Williams, Yves Pommier, Shar Yin N. Huang, Sue Jinks-Robertson, and Alan B. Clark

Subjects
DNA Replication, Saccharomyces cerevisiae Proteins, Transcription, Genetic, RNase P, Ribonucleotide excision repair, Molecular Sequence Data, Ribonuclease H, DNA, Single-Stranded, Saccharomyces cerevisiae, Nervous System Malformations, Article, chemistry.chemical_compound, Canavanine, Autoimmune Diseases of the Nervous System, Humans, RNase H, DNA, Fungal, Sequence Deletion, Multidisciplinary, biology, Base Sequence, Topoisomerase, DNA Breaks, RNA, Ribonucleotides, chemistry, Biochemistry, DNA Topoisomerases, Type I, Mutagenesis, biology.protein, Nucleic acid, DNA supercoil, Amino Acid Transport Systems, Basic, Nucleic Acid Conformation, Camptothecin, DNA, Microsatellite Repeats
Abstract

The ribonuclease (RNase) H class of enzymes degrades the RNA component of RNA:DNA hybrids and is important in nucleic acid metabolism. RNase H2 is specialized to remove single ribonucleotides [ribonucleoside monophosphates (rNMPs)] from duplex DNA, and its absence in budding yeast has been associated with the accumulation of deletions within short tandem repeats. Here, we demonstrate that rNMP-associated deletion formation requires the activity of Top1, a topoisomerase that relaxes supercoils by reversibly nicking duplex DNA. The reported studies extend the role of Top1 to include the processing of rNMPs in genomic DNA into irreversible single-strand breaks, an activity that can have distinct mutagenic consequences and may be relevant to human disease.

Published
2011

24. Gastrointestinal effects of 5-hydroxytryptamine and related drugs

Author

K. Mohan Dhasmana, Carlos M. Villalón, Silvia L. Cruz, and Yin N. Zhu

Subjects
Serotonin, medicine.medical_specialty, Gastrointestinal smooth muscle, Motility, Biology, Pharmacology, General Biochemistry, Genetics and Molecular Biology, Smooth muscle, Digestive System Physiological Phenomena, Internal medicine, medicine, Animals, heterocyclic compounds, General Pharmacology, Toxicology and Pharmaceutics, Receptor, Nervous control, Gastrointestinal tract, musculoskeletal, neural, and ocular physiology, Muscle, Smooth, General Medicine, musculoskeletal system, Endocrinology, nervous system, Receptors, Serotonin, Digestive System
Abstract

This paper deals with the effects of 5-hydroxytryptamine (5-HT; serotonin) and related drugs on the gastrointestinal tract (GIT). The nomenclature and classification of 5-HT receptors, as well as their putative role in the GIT are updated in this review. Besides its effects on the cardiovascular system, which have been extensively described, several lines of evidence suggest a role for 5-HT in regulating gastrointestinal functions. 5-HT is present in the gastrointestinal tissues, and can elicit contraction or relaxation by activation of a wide variety of mechanisms and receptors. At least four main types of receptors (5-HT1, 5-HT2, 5-HT3 and 5-HT4) have been described and all the four types seem to influence the GIT. In this respect, the 5-HT2, and in some cases the 5-HT1 receptors, appear to be present on the gastrointestinal smooth muscle, while 5-HT3 and 5-HT4 are mainly neuronal.

Published
1993

25. Abstract A257: Stereospecific trapping of PARP-DNA complexes by BMN 673 and comparison with olaparib and rucaparib

Author

Shar-yin N. Huang, Jiuping Ji, James H. Doroshow, Amelie Renaud, Shunichi Takeda, Yiping Zhang, Joel Morris, Beverly A. Teicher, Junko Murai, and Yves Pommier

Subjects
Cancer Research, Poly ADP ribose polymerase, fungi, Methane sulfonate, Biology, Virology, Olaparib, chemistry.chemical_compound, PARP1, Oncology, chemistry, PARP inhibitor, Cancer research, biology.protein, Rucaparib, DNA, Polymerase
Abstract

Anti-poly(ADP-ribose)polymerase (PARP) drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. Yet, several PARP inhibitors have an additional cytotoxic mechanism by trapping PARP-DNA complexes; both olaparib and niraparib act as PARP poisons at pharmacological concentrations (Murai et al., Cancer Res, 2012). Here, we evaluate the novel PARP inhibitor, BMN 673, and compare its effects on PARP1 and PARP2 with two other clinical PARP inhibitors, olaparib and rucaparib, using biochemical and cellular assays in genetically-modified chicken DT40 and human cancer cell lines. We show that BMN 673, olaparib, and rucaparib are similarly potent at inhibiting PARP catalytic activity. At the same time, BMN 673 is ∼100-fold more potent at trapping PARP-DNA complexes and more cytotoxic as a single agent than olaparib, while olaparib and rucaparib show similar potencies in trapping PARP-DNA complexes. The high level of resistance of PARP1/2 knockout cells to BMN 673 demonstrates the selectivity of BMN 673 for PARP1/2. Moreover, we show that BMN 673 acts by stereospecific binding to PARP1 as its enantiomer, LT674, is several orders of magnitude less efficient, and that BMN 673 is more cytotoxic than olaparib and rucaparib in combination with the DNA alkylating agents methyl methane sulfonate (MMS) and temozolomide. Our study demonstrates that BMN 673 is the most potent clinical PARP inhibitor to date with the highest efficiency at trapping PARP-DNA complexes. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A257. Citation Format: Junko Murai, Shar-yin N. Huang, Amelie Renaud, Yiping Zhang, Jiuping Ji, Shunichi Takeda, Joel Morris, Beverly Teicher, James H. Doroshow, Yves Pommier. Stereospecific trapping of PARP-DNA complexes by BMN 673 and comparison with olaparib and rucaparib. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A257.

Published
2013

26. Abstract C79: TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs

Author

William H. Gmeiner, Shar-yin N. Huang, Junko Murai, Ilaria Dalla Rosa, Thomas S. Dexheimer, and Yves Pommier

Subjects
Cancer Research, Mitochondrial DNA, Nucleoside analogue, DNA damage, DNA replication, Biology, Virology, Molecular biology, chemistry.chemical_compound, Zidovudine, Oncology, chemistry, medicine, Cytarabine, TDP1, DNA, medicine.drug
Abstract

Nucleoside analogs (NAs) that cause stalling or premature termination of DNA replication forks are widely used as anticancer and antiviral drugs. However, it is not well understood how cells repair the DNA damage induced by these chain-terminating NAs. Here we reveal the importance of tyrosyl-DNA phosphodiesterase 1 (TDP1) in the repair of nuclear and mitochondrial DNA damage induced by chain-terminating NAs. Upon investigating the effects of four NAs: acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT) and zalcitabine (ddC), we show that TDP1 is capable of removing the covalently-linked corresponding NAs from DNA 3’-ends. We also show that Tdp1–/– cells are hypersensitive and accumulate more DNA damage when treated with ACV and Ara-C, implicating TDP1 in repairing NA-induced DNA damage. Since AZT and ddC are known to cause mitochondrial dysfunction, we examined whether TDP1 repairs the mitochondrial DNA damage they induced. We found that AZT and ddC treatment leads to greater depletion of mitochondrial DNA in Tdp1–/– cells. Thus, TDP1 appears critical for repairing nuclear and mitochondrial DNA damage caused by chain-terminating NAs. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C79. Citation Format: Shar-Yin N. Huang, Junko Murai, Ilaria Dalla Rosa, Thomas S. Dexheimer, William H. Gmeiner, Yves Pommier. TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C79.

Published
2013

27. A genetically encoded photocaged Nε-methyl-l-lysine

Author

Ying Huang, Wei Wan, Yane-Shih Wang, Bo Wu, David H. Russell, William K. Russell, Yin N. Moe, Zhiyong Wang, Pei Jing Pai, and Wenshe R. Liu

Subjects
Electrospray ionization, Lysine, Lysine metabolism, Protein engineering, Biology, medicine.disease_cause, Mass spectrometry, complex mixtures, Stop codon, chemistry.chemical_compound, Biosynthesis, chemistry, Biochemistry, medicine, bacteria, Molecular Biology, Escherichia coli, Biotechnology
Abstract

A photocaged N(epsilon)-methyl-L-lysine has been genetically incorporated into proteins at amber codon positions in Escherichia coli using an evolved pyrrolysyl-tRNA synthetase-pylT pair. Its genetic incorporation and following photolysis to recover N(epsilon)-methyl-L-lysine at physiological pH provide a convenient method for the biosynthesis of proteins with monomethylated lysines at specific sites.

Published
2010

28. The Design and Sensitivity of JUNO's scintillator radiopurity pre-detector OSIRIS

Author

JUNO Collaboration, Abusleme, Angel, Adam, Thomas, Ahmad, Shakeel, Ahmed, Rizwan, Aiello, Sebastiano, Akram, Muhammad, An, Fengpeng, An, Guangpeng, An, Qi, Andronico, Giuseppe, Anfimov, Nikolay, Antonelli, Vito, Antoshkina, Tatiana, Asavapibhop, Burin, de André, João Pedro Athayde Marcondes, Auguste, Didier, Babic, Andrej, Baldini, Wander, Barresi, Andrea, Basilico, Davide, Baussan, Eric, Bellato, Marco, Bergnoli, Antonio, Birkenfeld, Thilo, Blin, Sylvie, Blum, David, Blyth, Simon, Bolshakova, Anastasia, Bongrand, Mathieu, Bordereau, Clément, Breton, Dominique, Brigatti, Augusto, Brugnera, Riccardo, Bruno, Riccardo, Budano, Antonio, Buscemi, Mario, Busto, Jose, Butorov, Ilya, Cabrera, Anatael, Cai, Hao, Cai, Xiao, Cai, Yanke, Cai, Zhiyan, Cammi, Antonio, Campeny, Agustin, Cao, Chuanya, Cao, Guofu, Cao, Jun, Caruso, Rossella, Cerna, Cédric, Chang, Jinfan, Chang, Yun, Chen, Pingping, Chen, Po-An, Chen, Shaomin, Chen, Xurong, Chen, Yi-Wen, Chen, Yixue, Chen, Yu, Chen, Zhang, Cheng, Jie, Cheng, Yaping, Chetverikov, Alexey, Chiesa, Davide, Chimenti, Pietro, Chukanov, Artem, Claverie, Gérard, Clementi, Catia, Clerbaux, Barbara, Di Lorenzo, Selma Conforti, Corti, Daniele, Costa, Salvatore, Corso, Flavio Dal, Dalager, Olivia, De La Taille, Christophe, Deng, Jiawei, Deng, Zhi, Deng, Ziyan, Depnering, Wilfried, Diaz, Marco, Ding, Xuefeng, Ding, Yayun, Dirgantara, Bayu, Dmitrievsky, Sergey, Dohnal, Tadeas, Dolzhikov, Dmitry, Donchenko, Georgy, Dong, Jianmeng, Doroshkevich, Evgeny, Dracos, Marcos, Druillole, Frédéric, Du, Shuxian, Dusini, Stefano, Dvorak, Martin, Enqvist, Timo, Enzmann, Heike, Fabbri, Andrea, Fajt, Lukas, Fan, Donghua, Fan, Lei, Fang, Can, Fang, Jian, Fang, Wenxing, Fargetta, Marco, Fedoseev, Dmitry, Fekete, Vladko, Feng, Li-Cheng, Feng, Qichun, Ford, Richard, Formozov, Andrey, Fournier, Amélie, Gan, Haonan, Gao, Feng, Garfagnini, Alberto, Genster, Christoph, Giammarchi, Marco, Giaz, Agnese, Giudice, Nunzio, Gonchar, Maxim, Gong, Guanghua, Gong, Hui, Gornushkin, Yuri, Göttel, Alexandre, Grassi, Marco, Grewing, Christian, Gromov, Vasily, Gu, Minghao, Gu, Xiaofei, Gu, Yu, Guan, Mengyun, Guardone, Nunzio, Gul, Maria, Guo, Cong, Guo, Jingyuan, Guo, Wanlei, Guo, Xinheng, Guo, Yuhang, Hackspacher, Paul, Hagner, Caren, Han, Ran, Han, Yang, Hassan, Muhammad Sohaib, He, Miao, He, Wei, Heinz, Tobias, Hellmuth, Patrick, Heng, Yuekun, Herrera, Rafael, Hong, Daojin, Hor, YuenKeung, Hou, Shaojing, Hsiung, Yee, Hu, Bei-Zhen, Hu, Hang, Hu, Jianrun, Hu, Jun, Hu, Shouyang, Hu, Tao, Hu, Zhuojun, Huang, Chunhao, Huang, Guihong, Huang, Hanxiong, Huang, Wenhao, Huang, Xin, Huang, Xingtao, Huang, Yongbo, Hui, Jiaqi, Huo, Lei, Huo, Wenju, Huss, Cédric, Hussain, Safeer, Ioannisian, Ara, Isocrate, Roberto, Jelmini, Beatrice, Jen, Kuo-Lun, Jeria, Ignacio, Ji, Xiaolu, Ji, Xingzhao, Jia, Huihui, Jia, Junji, Jian, Siyu, Jiang, Di, Jiang, Xiaoshan, Jin, Ruyi, Jing, Xiaoping, Jollet, Cécile, Joutsenvaara, Jari, Jungthawan, Sirichok, Kalousis, Leonidas, Kampmann, Philipp, Kang, Li, Karagounis, Michael, Kazarian, Narine, Khan, Waseem, Khosonthongkee, Khanchai, Korablev, Denis, Kouzakov, Konstantin, Krasnoperov, Alexey, Kruth, Andre, Kutovskiy, Nikolay, Kuusiniemi, Pasi, Lachenmaier, Tobias, Landini, Cecilia, Leblanc, Sébastien, Lebrin, Victor, Lefevre, Frederic, Lei, Ruiting, Leitner, Rupert, Leung, Jason, Li, Demin, Li, Fei, Li, Fule, Li, Haitao, Li, Huiling, Li, Jiaqi, Li, Mengzhao, Li, Min, Li, Nan, Li, Qingjiang, Li, Ruhui, Li, Shanfeng, Li, Tao, Li, Weidong, Li, Weiguo, Li, Xiaomei, Li, Xiaonan, Li, Xinglong, Li, Yi, Li, Yufeng, Li, Zhaohan, Li, Zhibing, Li, Ziyuan, Liang, Hao, Liang, Jingjing, Liao, Jiajun, Liebau, Daniel, Limphirat, Ayut, Limpijumnong, Sukit, Lin, Guey-Lin, Lin, Shengxin, Lin, Tao, Ling, Jiajie, Lippi, Ivano, Liu, Fang, Liu, Haidong, Liu, Hongbang, Liu, Hongjuan, Liu, Hongtao, Liu, Hui, Liu, Jianglai, Liu, Jinchang, Liu, Min, Liu, Qian, Liu, Qin, Liu, Runxuan, Liu, Shuangyu, Liu, Shubin, Liu, Shulin, Liu, Xiaowei, Liu, Xiwen, Liu, Yan, Liu, Yunzhe, Lokhov, Alexey, Lombardi, Paolo, Lombardo, Claudio, Loo, Kai, Lu, Chuan, Lu, Haoqi, Lu, Jingbin, Lu, Junguang, Lu, Shuxiang, Lu, Xiaoxu, Lubsandorzhiev, Bayarto, Lubsandorzhiev, Sultim, Ludhova, Livia, Luo, Fengjiao, Luo, Guang, Luo, Pengwei, Luo, Shu, Luo, Wuming, Lyashuk, Vladimir, Ma, Bangzheng, Ma, Qiumei, Ma, Si, Ma, Xiaoyan, Ma, Xubo, Maalmi, Jihane, Malyshkin, Yury, Mantovani, Fabio, Manzali, Francesco, Mao, Xin, Mao, Yajun, Mari, Stefano M., Marini, Filippo, Marium, Sadia, Martellini, Cristina, Martin-Chassard, Gisele, Martini, Agnese, Mayilyan, Davit, Mednieks, Ints, Meng, Yue, Meregaglia, Anselmo, Meroni, Emanuela, Meyhöfer, David, Mezzetto, Mauro, Miller, Jonathan, Miramonti, Lino, Montini, Paolo, Montuschi, Michele, Müller, Axel, Muralidharan, Pavithra, Nastasi, Massimiliano, Naumov, Dmitry V., Naumova, Elena, Navas-Nicolas, Diana, Nemchenok, Igor, NguyenThi, MinhThuan, Ning, Feipeng, Ning, Zhe, Nunokawa, Hiroshi, Oberauer, Lothar, Ochoa-Ricoux, Juan Pedro, Olshevskiy, Alexander, Orestano, Domizia, Ortica, Fausto, Othegraven, Rainer, Pan, Hsiao-Ru, Paoloni, Alessandro, Parkalian, Nina, Parmeggiano, Sergio, Pei, Yatian, Pelliccia, Nicomede, Peng, Anguo, Peng, Haiping, Perrot, Frédéric, Petitjean, Pierre-Alexandre, Petrucci, Fabrizio, Pilarczyk, Oliver, Rico, Luis Felipe Piñeres, Popov, Artyom, Poussot, Pascal, Pratumwan, Wathan, Previtali, Ezio, Qi, Fazhi, Qi, Ming, Qian, Sen, Qian, Xiaohui, Qian, Zhen, Qiao, Hao, Qin, Zhonghua, Qiu, Shoukang, Rajput, Muhammad Usman, Ranucci, Gioacchino, Raper, Neill, Re, Alessandra, Rebber, Henning, Rebii, Abdel, Ren, Bin, Ren, Jie, Ricci, Barbara, Robens, Markus, Roche, Mathieu, Rodphai, Narongkiat, Romani, Aldo, Roskovec, Bedřich, Roth, Christian, Ruan, Xiangdong, Ruan, Xichao, Rujirawat, Saroj, Rybnikov, Arseniy, Sadovsky, Andrey, Saggese, Paolo, Sanfilippo, Simone, Sangka, Anut, Sanguansak, Nuanwan, Sawangwit, Utane, Sawatzki, Julia, Sawy, Fatma, Schever, Michaela, Schwab, Cédric, Schweizer, Konstantin, Selyunin, Alexandr, Serafini, Andrea, Settanta, Giulio, Settimo, Mariangela, Shao, Zhuang, Sharov, Vladislav, Shaydurova, Arina, Shi, Jingyan, Shi, Yanan, Shutov, Vitaly, Sidorenkov, Andrey, Šimkovic, Fedor, Sirignano, Chiara, Siripak, Jaruchit, Sisti, Monica, Slupecki, Maciej, Smirnov, Mikhail, Smirnov, Oleg, Sogo-Bezerra, Thiago, Sokolov, Sergey, Songwadhana, Julanan, Soonthornthum, Boonrucksar, Sotnikov, Albert, Šrámek, Ondřej, Sreethawong, Warintorn, Stahl, Achim, Stanco, Luca, Stankevich, Konstantin, Štefánik, Dušan, Steiger, Hans, Steinmann, Jochen, Sterr, Tobias, Stock, Matthias Raphael, Strati, Virginia, Studenikin, Alexander, Sun, Gongxing, Sun, Shifeng, Sun, Xilei, Sun, Yongjie, Sun, Yongzhao, Suwonjandee, Narumon, Szelezniak, Michal, Tang, Jian, Tang, Qiang, Tang, Quan, Tang, Xiao, Tietzsch, Alexander, Tkachev, Igor, Tmej, Tomas, Treskov, Konstantin, Triossi, Andrea, Troni, Giancarlo, Trzaska, Wladyslaw, Tuve, Cristina, Ushakov, Nikita, Boom, Johannes van den, van Waasen, Stefan, Vanroyen, Guillaume, Vassilopoulos, Nikolaos, Vedin, Vadim, Verde, Giuseppe, Vialkov, Maxim, Viaud, Benoit, Vollbrecht, Cornelius, Volpe, Cristina, Vorobel, Vit, Voronin, Dmitriy, Votano, Lucia, Walker, Pablo, Wang, Caishen, Wang, Chung-Hsiang, Wang, En, Wang, Guoli, Wang, Jian, Wang, Jun, Wang, Kunyu, Wang, Lu, Wang, Meifen, Wang, Meng, Wang, Ruiguang, Wang, Siguang, Wang, Wei, Wang, Wenshuai, Wang, Xi, Wang, Xiangyue, Wang, Yangfu, Wang, Yaoguang, Wang, Yi, Wang, Yifang, Wang, Yuanqing, Wang, Yuman, Wang, Zhe, Wang, Zheng, Wang, Zhimin, Wang, Zongyi, Waqas, Muhammad, Watcharangkool, Apimook, Wei, Lianghong, Wei, Wei, Wei, Wenlu, Wei, Yadong, Wen, Liangjian, Wiebusch, Christopher, Wong, Steven Chan-Fai, Wonsak, Bjoern, Wu, Diru, Wu, Fangliang, Wu, Qun, Wu, Zhi, Wurm, Michael, Wurtz, Jacques, Wysotzki, Christian, Xi, Yufei, Xia, Dongmei, Xie, Yuguang, Xie, Zhangquan, Xing, Zhizhong, Xu, Benda, Xu, Cheng, Xu, Donglian, Xu, Fanrong, Xu, Hangkun, Xu, Jilei, Xu, Jing, Xu, Meihang, Xu, Yin, Xu, Yu, Yan, Baojun, Yan, Taylor, Yan, Wenqi, Yan, Xiongbo, Yan, Yupeng, Yang, Anbo, Yang, Changgen, Yang, Huan, Yang, Jie, Yang, Lei, Yang, Xiaoyu, Yang, Yifan, Yao, Haifeng, Yasin, Zafar, Ye, Jiaxuan, Ye, Mei, Ye, Ziping, Yegin, Ugur, Yermia, Frédéric, Yi, Peihuai, Yin, Na, Yin, Xiangwei, You, Zhengyun, Yu, Boxiang, Yu, Chiye, Yu, Chunxu, Yu, Hongzhao, Yu, Miao, Yu, Xianghui, Yu, Zeyuan, Yu, Zezhong, Yuan, Chengzhuo, Yuan, Ying, Yuan, Zhenxiong, Yuan, Ziyi, Yue, Baobiao, Zafar, Noman, Zambanini, Andre, Zavadskyi, Vitalii, Zeng, Shan, Zeng, Tingxuan, Zeng, Yuda, Zhan, Liang, Zhang, Aiqiang, Zhang, Feiyang, Zhang, Guoqing, Zhang, Haiqiong, Zhang, Honghao, Zhang, Jiawen, Zhang, Jie, Zhang, Jingbo, Zhang, Jinnan, Zhang, Peng, Zhang, Qingmin, Zhang, Shiqi, Zhang, Shu, Zhang, Tao, Zhang, Xiaomei, Zhang, Xuantong, Zhang, Xueyao, Zhang, Yan, Zhang, Yinhong, Zhang, Yiyu, Zhang, Yongpeng, Zhang, Yuanyuan, Zhang, Yumei, Zhang, Zhenyu, Zhang, Zhijian, Zhao, Fengyi, Zhao, Jie, Zhao, Rong, Zhao, Shujun, Zhao, Tianchi, Zheng, Dongqin, Zheng, Hua, Zheng, Minshan, Zheng, Yangheng, Zhong, Weirong, Zhou, Jing, Zhou, Li, Zhou, Nan, Zhou, Shun, Zhou, Tong, Zhou, Xiang, Zhu, Jiang, Zhu, Kangpu, Zhu, Kejun, Zhu, Zhihang, Zhuang, Bo, Zhuang, Honglin, Zong, Liang, Zou, Jiaheng, Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique des 2 Infinis Irène Joliot-Curie (IJCLab), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de physique subatomique et des technologies associées (SUBATECH), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Centre d'Etudes Nucléaires de Bordeaux Gradignan (CENBG), Université Sciences et Technologies - Bordeaux 1-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Centre de Physique des Particules de Marseille (CPPM), Aix Marseille Université (AMU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), JUNO, Abusleme, A, Adam, T, Ahmad, S, Ahmed, R, Aiello, S, Akram, M, An, F, An, G, An, Q, Andronico, G, Anfimov, N, Antonelli, V, Antoshkina, T, Asavapibhop, B, de Andre, J, Auguste, D, Babic, A, Baldini, W, Barresi, A, Basilico, D, Baussan, E, Bellato, M, Bergnoli, A, Birkenfeld, T, Blin, S, Blum, D, Blyth, S, Bolshakova, A, Bongrand, M, Bordereau, C, Breton, D, Brigatti, A, Brugnera, R, Bruno, R, Budano, A, Buscemi, M, Busto, J, Butorov, I, Cabrera, A, Cai, H, Cai, X, Cai, Y, Cai, Z, Cammi, A, Campeny, A, Cao, C, Cao, G, Cao, J, Caruso, R, Cerna, C, Chang, J, Chang, Y, Chen, P, Chen, S, Chen, X, Chen, Y, Chen, Z, Cheng, J, Cheng, Y, Chetverikov, A, Chiesa, D, Chimenti, P, Chukanov, A, Claverie, G, Clementi, C, Clerbaux, B, Lorenzo, S, Corti, D, Costa, S, Corso, F, Dalager, O, De La Taille, C, Deng, J, Deng, Z, Depnering, W, Diaz, M, Ding, X, Ding, Y, Dirgantara, B, Dmitrievsky, S, Dohnal, T, Dolzhikov, D, Donchenko, G, Dong, J, Doroshkevich, E, Dracos, M, Druillole, F, Du, S, Dusini, S, Dvorak, M, Enqvist, T, Enzmann, H, Fabbri, A, Fajt, L, Fan, D, Fan, L, Fang, C, Fang, J, Fang, W, Fargetta, M, Fedoseev, D, Fekete, V, Feng, L, Feng, Q, Ford, R, Formozov, A, Fournier, A, Gan, H, Gao, F, Garfagnini, A, Genster, C, Giammarchi, M, Giaz, A, Giudice, N, Gonchar, M, Gong, G, Gong, H, Gornushkin, Y, Gottel, A, Grassi, M, Grewing, C, Gromov, V, Gu, M, Gu, X, Gu, Y, Guan, M, Guardone, N, Gul, M, Guo, C, Guo, J, Guo, W, Guo, X, Guo, Y, Hackspacher, P, Hagner, C, Han, R, Han, Y, Hassan, M, He, M, He, W, Heinz, T, Hellmuth, P, Heng, Y, Herrera, R, Hong, D, Hor, Y, Hou, S, Hsiung, Y, Hu, B, Hu, H, Hu, J, Hu, S, Hu, T, Hu, Z, Huang, C, Huang, G, Huang, H, Huang, W, Huang, X, Huang, Y, Hui, J, Huo, L, Huo, W, Huss, C, Hussain, S, Ioannisian, A, Isocrate, R, Jelmini, B, Jen, K, Jeria, I, Ji, X, Jia, H, Jia, J, Jian, S, Jiang, D, Jiang, X, Jin, R, Jing, X, Jollet, C, Joutsenvaara, J, Jungthawan, S, Kalousis, L, Kampmann, P, Kang, L, Karagounis, M, Kazarian, N, Khan, W, Khosonthongkee, K, Korablev, D, Kouzakov, K, Krasnoperov, A, Kruth, A, Kutovskiy, N, Kuusiniemi, P, Lachenmaier, T, Landini, C, Leblanc, S, Lebrin, V, Lefevre, F, Lei, R, Leitner, R, Leung, J, Li, D, Li, F, Li, H, Li, J, Li, M, Li, N, Li, Q, Li, R, Li, S, Li, T, Li, W, Li, X, Li, Y, Li, Z, Liang, H, Liang, J, Liao, J, Liebau, D, Limphirat, A, Limpijumnong, S, Lin, G, Lin, S, Lin, T, Ling, J, Lippi, I, Liu, F, Liu, H, Liu, J, Liu, M, Liu, Q, Liu, R, Liu, S, Liu, X, Liu, Y, Lokhov, A, Lombardi, P, Lombardo, C, Loo, K, Lu, C, Lu, H, Lu, J, Lu, S, Lu, X, Lubsandorzhiev, B, Lubsandorzhiev, S, Ludhova, L, Luo, F, Luo, G, Luo, P, Luo, S, Luo, W, Lyashuk, V, Ma, B, Ma, Q, Ma, S, Ma, X, Maalmi, J, Malyshkin, Y, Mantovani, F, Manzali, F, Mao, X, Mao, Y, Mari, S, Marini, F, Marium, S, Martellini, C, Martin-Chassard, G, Martini, A, Mayilyan, D, Mednieks, I, Meng, Y, Meregaglia, A, Meroni, E, Meyhofer, D, Mezzetto, M, Miller, J, Miramonti, L, Montini, P, Montuschi, M, Muller, A, Muralidharan, P, Nastasi, M, Naumov, D, Naumova, E, Navas-Nicolas, D, Nemchenok, I, Nguyenthi, M, Ning, F, Ning, Z, Nunokawa, H, Oberauer, L, Ochoa-Ricoux, J, Olshevskiy, A, Orestano, D, Ortica, F, Othegraven, R, Pan, H, Paoloni, A, Parkalian, N, Parmeggiano, S, Pei, Y, Pelliccia, N, Peng, A, Peng, H, Perrot, F, Petitjean, P, Petrucci, F, Pilarczyk, O, Rico, L, Popov, A, Poussot, P, Pratumwan, W, Previtali, E, Qi, F, Qi, M, Qian, S, Qian, X, Qian, Z, Qiao, H, Qin, Z, Qiu, S, Rajput, M, Ranucci, G, Raper, N, Re, A, Rebber, H, Rebii, A, Ren, B, Ren, J, Ricci, B, Robens, M, Roche, M, Rodphai, N, Romani, A, Roskovec, B, Roth, C, Ruan, X, Rujirawat, S, Rybnikov, A, Sadovsky, A, Saggese, P, Sanfilippo, S, Sangka, A, Sanguansak, N, Sawangwit, U, Sawatzki, J, Sawy, F, Schever, M, Schwab, C, Schweizer, K, Selyunin, A, Serafini, A, Settanta, G, Settimo, M, Shao, Z, Sharov, V, Shaydurova, A, Shi, J, Shi, Y, Shutov, V, Sidorenkov, A, Simkovic, F, Sirignano, C, Siripak, J, Sisti, M, Slupecki, M, Smirnov, M, Smirnov, O, Sogo-Bezerra, T, Sokolov, S, Songwadhana, J, Soonthornthum, B, Sotnikov, A, Sramek, O, Sreethawong, W, Stahl, A, Stanco, L, Stankevich, K, Stefanik, D, Steiger, H, Steinmann, J, Sterr, T, Stock, M, Strati, V, Studenikin, A, Sun, G, Sun, S, Sun, X, Sun, Y, Suwonjandee, N, Szelezniak, M, Tang, J, Tang, Q, Tang, X, Tietzsch, A, Tkachev, I, Tmej, T, Treskov, K, Triossi, A, Troni, G, Trzaska, W, Tuve, C, Ushakov, N, van den Boom, J, van Waasen, S, Vanroyen, G, Vassilopoulos, N, Vedin, V, Verde, G, Vialkov, M, Viaud, B, Vollbrecht, C, Volpe, C, Vorobel, V, Voronin, D, Votano, L, Walker, P, Wang, C, Wang, E, Wang, G, Wang, J, Wang, K, Wang, L, Wang, M, Wang, R, Wang, S, Wang, W, Wang, X, Wang, Y, Wang, Z, Waqas, M, Watcharangkool, A, Wei, L, Wei, W, Wei, Y, Wen, L, Wiebusch, C, Wong, S, Wonsak, B, Wu, D, Wu, F, Wu, Q, Wu, Z, Wurm, M, Wurtz, J, Wysotzki, C, Xi, Y, Xia, D, Xie, Y, Xie, Z, Xing, Z, Xu, B, Xu, C, Xu, D, Xu, F, Xu, H, Xu, J, Xu, M, Xu, Y, Yan, B, Yan, T, Yan, W, Yan, X, Yan, Y, Yang, A, Yang, C, Yang, H, Yang, J, Yang, L, Yang, X, Yang, Y, Yao, H, Yasin, Z, Ye, J, Ye, M, Ye, Z, Yegin, U, Yermia, F, Yi, P, Yin, N, Yin, X, You, Z, Yu, B, Yu, C, Yu, H, Yu, M, Yu, X, Yu, Z, Yuan, C, Yuan, Y, Yuan, Z, Yue, B, Zafar, N, Zambanini, A, Zavadskyi, V, Zeng, S, Zeng, T, Zeng, Y, Zhan, L, Zhang, A, Zhang, F, Zhang, G, Zhang, H, Zhang, J, Zhang, P, Zhang, Q, Zhang, S, Zhang, T, Zhang, X, Zhang, Y, Zhang, Z, Zhao, F, Zhao, J, Zhao, R, Zhao, S, Zhao, T, Zheng, D, Zheng, H, Zheng, M, Zheng, Y, Zhong, W, Zhou, J, Zhou, L, Zhou, N, Zhou, S, Zhou, T, Zhou, X, Zhu, J, Zhu, K, Zhu, Z, Zhuang, B, Zhuang, H, Zong, L, Zou, J, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Nantes université - UFR des Sciences et des Techniques (Nantes univ - UFR ST), Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Abusleme, Angel, Adam, Thoma, Ahmad, Shakeel, Ahmed, Rizwan, Aiello, Sebastiano, Akram, Muhammad, An, Fengpeng, An, Guangpeng, An, Qi, Andronico, Giuseppe, Anfimov, Nikolay, Antonelli, Vito, Antoshkina, Tatiana, Asavapibhop, Burin, de André, João Pedro Athayde Marconde, Auguste, Didier, Babic, Andrej, Baldini, Wander, Barresi, Andrea, Basilico, Davide, Baussan, Eric, Bellato, Marco, Bergnoli, Antonio, Birkenfeld, Thilo, Blin, Sylvie, Blum, David, Blyth, Simon, Bolshakova, Anastasia, Bongrand, Mathieu, Bordereau, Clément, Breton, Dominique, Brigatti, Augusto, Brugnera, Riccardo, Bruno, Riccardo, Budano, Antonio, Buscemi, Mario, 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Brugnera R., Bruno R., Budano A., Buscemi M., Busto J., Butorov I., Cabrera A., Cai H., Cai X., Cai Y., Cai Z., Cammi A., Campeny A., Cao C., Cao G., Cao J., Caruso R., Cerna C., Chang J., Chang Y., Chen P., Chen P.-A., Chen S., Chen X., Chen Y.-W., Chen Y., Chen Z., Cheng J., Cheng Y., Chetverikov A., Chiesa D., Chimenti P., Chukanov A., Claverie G., Clementi C., Clerbaux B., Lorenzo S.C.D., Corti D., Costa S., Corso F.D., Dalager O., De La Taille C., Deng J., Deng Z., Depnering W., Diaz M., Ding X., Ding Y., Dirgantara B., Dmitrievsky S., Dohnal T., Dolzhikov D., Donchenko G., Dong J., Doroshkevich E., Dracos M., Druillole F., Du S., Dusini S., Dvorak M., Enqvist T., Enzmann H., Fabbri A., Fajt L., Fan D., Fan L., Fang C., Fang J., Fang W., Fargetta M., Fedoseev D., Fekete V., Feng L.-C., Feng Q., Ford R., Formozov A., Fournier A., Gan H., Gao F., Garfagnini A., Genster C., Giammarchi M., Giaz A., Giudice N., Gonchar M., Gong G., Gong H., Gornushkin Y., Gottel A., Grassi M., Grewing C., Gromov V., Gu M., Gu X., Gu Y., Guan M., Guardone N., Gul M., Guo C., Guo J., Guo W., Guo X., Guo Y., Hackspacher P., Hagner C., Han R., Han Y., Hassan M.S., He M., He W., Heinz T., Hellmuth P., Heng Y., Herrera R., Hong D., Hor Y.K., Hou S., Hsiung Y., Hu B.-Z., Hu H., Hu J., Hu S., Hu T., Hu Z., Huang C., Huang G., Huang H., Huang W., Huang X., Huang Y., Hui J., Huo L., Huo W., Huss C., Hussain S., Ioannisian A., Isocrate R., Jelmini B., Jen K.-L., Jeria I., Ji X., Jia H., Jia J., Jian S., Jiang D., Jiang X., Jin R., Jing X., Jollet C., Joutsenvaara J., Jungthawan S., Kalousis L., Kampmann P., Kang L., Karagounis M., Kazarian N., Khan W., Khosonthongkee K., Korablev D., Kouzakov K., Krasnoperov A., Kruth A., Kutovskiy N., Kuusiniemi P., Lachenmaier T., Landini C., Leblanc S., Lebrin V., Lefevre F., Lei R., Leitner R., Leung J., Li D., Li F., Li H., Li J., Li M., Li N., Li Q., Li R., Li S., Li T., Li W., Li X., Li Y., Li Z., Liang H., Liang J., Liao J., Liebau D., Limphirat A., 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Pilarczyk O., Rico L.F.P., Popov A., Poussot P., Pratumwan W., Previtali E., Qi F., Qi M., Qian S., Qian X., Qian Z., Qiao H., Qin Z., Qiu S., Rajput M.U., Ranucci G., Raper N., Re A., Rebber H., Rebii A., Ren B., Ren J., Ricci B., Robens M., Roche M., Rodphai N., Romani A., Roskovec B., Roth C., Ruan X., Rujirawat S., Rybnikov A., Sadovsky A., Saggese P., Sanfilippo S., Sangka A., Sanguansak N., Sawangwit U., Sawatzki J., Sawy F., Schever M., Schwab C., Schweizer K., Selyunin A., Serafini A., Settanta G., Settimo M., Shao Z., Sharov V., Shaydurova A., Shi J., Shi Y., Shutov V., Sidorenkov A., Simkovic F., Sirignano C., Siripak J., Sisti M., Slupecki M., Smirnov M., Smirnov O., Sogo-Bezerra T., Sokolov S., Songwadhana J., Soonthornthum B., Sotnikov A., Sramek O., Sreethawong W., Stahl A., Stanco L., Stankevich K., Stefanik D., Steiger H., Steinmann J., Sterr T., Stock M.R., Strati V., Studenikin A., Sun G., Sun S., Sun X., Sun Y., Suwonjandee N., Szelezniak M., Tang J., Tang Q., Tang X., Tietzsch A., Tkachev I., Tmej T., Treskov K., Triossi A., Troni G., Trzaska W., Tuve C., Ushakov N., van den Boom J., van Waasen S., Vanroyen G., Vassilopoulos N., Vedin V., Verde G., Vialkov M., Viaud B., Vollbrecht C., Volpe C., Vorobel V., Voronin D., Votano L., Walker P., Wang C., Wang C.-H., Wang E., Wang G., Wang J., Wang K., Wang L., Wang M., Wang R., Wang S., Wang W., Wang X., Wang Y., Wang Z., Waqas M., Watcharangkool A., Wei L., Wei W., Wei Y., Wen L., Wiebusch C., Wong S.C.-F., Wonsak B., Wu D., Wu F., Wu Q., Wu Z., Wurm M., Wurtz J., Wysotzki C., Xi Y., Xia D., Xie Y., Xie Z., Xing Z., Xu B., Xu C., Xu D., Xu F., Xu H., Xu J., Xu M., Xu Y., Yan B., Yan T., Yan W., Yan X., Yan Y., Yang A., Yang C., Yang H., Yang J., Yang L., Yang X., Yang Y., Yao H., Yasin Z., Ye J., Ye M., Ye Z., Yegin U., Yermia F., Yi P., Yin N., Yin X., You Z., Yu B., Yu C., Yu H., Yu M., Yu X., Yu Z., Yuan C., Yuan Y., Yuan Z., Yue B., Zafar N., Zambanini A., Zavadskyi V., Zeng S., Zeng T., Zeng Y., Zhan L., Zhang A., Zhang F., Zhang G., Zhang H., Zhang J., Zhang P., Zhang Q., Zhang S., Zhang T., Zhang X., Zhang Y., Zhang Z., Zhao F., Zhao J., Zhao R., Zhao S., Zhao T., Zheng D., Zheng H., Zheng M., Zheng Y., Zhong W., Zhou J., Zhou L., Zhou N., Zhou S., Zhou T., Zhou X., Zhu J., Zhu K., Zhu Z., Zhuang B., Zhuang H., Zong L., and Zou J.

Subjects
Liquid scintillator, Physics - Instrumentation and Detectors, Physics and Astronomy (miscellaneous), Physics::Instrumentation and Detectors, scintillation counter: liquid, measurement methods, QC770-798, Astrophysics, 01 natural sciences, thorium: nuclide, design [detector], neutrino, Radioactive purity, Physics, Low energy neutrino, JUNO, liquid [scintillation counter], biology, Settore FIS/01 - Fisica Sperimentale, Detector, Instrumentation and Detectors (physics.ins-det), 3. Good health, QB460-466, Physics::Space Physics, nuclide [uranium], FOS: Physical sciences, Scintillator, nuclide [thorium], NO, Nuclear physics, PE2_2, uranium: nuclide, Nuclear and particle physics. Atomic energy. Radioactivity, 0103 physical sciences, ddc:530, Sensitivity (control systems), [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], 010306 general physics, JUNO, neutrino physics, liquid scintillator, Engineering (miscellaneous), background: radioactivity, detector: design, Measurement method, 010308 nuclear & particles physics, radioactivity [background], biology.organism_classification, sensitivity, High Energy Physics::Experiment, Reactor neutrino, Osiris
Abstract

The European physical journal / C 81(11), 973 (2021). doi:10.1140/epjc/s10052-021-09544-4, The OSIRIS detector is a subsystem of the liquid scintillator filling chain of the JUNO reactor neutrino experiment. Its purpose is to validate the radiopurity of the scintillator to assure that all components of the JUNO scintillator system work to specifications and only neutrino-grade scintillator is filled into the JUNO Central Detector. The aspired sensitivity level of $10^{���16}$ g/g of $^{238}$U and $^{232}$Th requires a large (���20 m$^3$) detection volume and ultralow background levels. The present paper reports on the design and major components of the OSIRIS detector, the detector simulation as well as the measuring strategies foreseen and the sensitivity levels to U/Th that can be reached in this setup., Published by Springer, Heidelberg

Published
2021

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