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Article ; Online: A lentiviral vector for the production of T cells with an inducible transgene and a constitutively expressed tumour-targeting receptor.

Reichenbach, Patrick / Giordano Attianese, Greta Maria Paola / Ouchen, Khaoula / Cribioli, Elisabetta / Triboulet, Melanie / Ash, Sarah / Saillard, Margaux / Vuillefroy de Silly, Romain / Coukos, George / Irving, Melita

Nature biomedical engineering

2023 Volume 7, Issue 9, Page(s) 1063–1080

Abstract: Vectors that facilitate the engineering of T cells that can better harness endogenous immunity and overcome suppressive barriers in the tumour microenvironment would help improve the safety and efficacy of T-cell therapies for more patients. Here we ... ...

Abstract	Vectors that facilitate the engineering of T cells that can better harness endogenous immunity and overcome suppressive barriers in the tumour microenvironment would help improve the safety and efficacy of T-cell therapies for more patients. Here we report the design, production and applicability, in T-cell engineering, of a lentiviral vector leveraging an antisense configuration and comprising a promoter driving the constitutive expression of a tumour-directed receptor and a second promoter enabling the efficient activation-inducible expression of a genetic payload. The vector allows for the delivery of a variety of genes to human T cells, as we show for interleukin-2 and a microRNA-based short hairpin RNA for the knockdown of the gene coding for haematopoietic progenitor kinase 1, a negative regulator of T-cell-receptor signalling. We also show that a gene encoded under an activation-inducible promoter is specifically expressed by tumour-redirected T cells on encountering a target antigen in the tumour microenvironment. The single two-gene-encoding vector can be produced at high titres under an optimized protocol adaptable to good manufacturing practices.
MeSH term(s)	Humans ; Lentivirus/genetics ; T-Lymphocytes ; Transgenes/genetics ; Promoter Regions, Genetic/genetics ; Neoplasms/genetics ; Neoplasms/therapy ; Tumor Microenvironment
Language	English
Publishing date	2023-04-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2157-846X
ISSN (online)	2157-846X
DOI	10.1038/s41551-023-01013-5
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: TCR sequencing and cloning methods for repertoire analysis and isolation of tumor-reactive TCRs.

Genolet, Raphael / Bobisse, Sara / Chiffelle, Johanna / Arnaud, Marion / Petremand, Rémy / Queiroz, Lise / Michel, Alexandra / Reichenbach, Patrick / Cesbron, Julien / Auger, Aymeric / Baumgaertner, Petra / Guillaume, Philippe / Schmidt, Julien / Irving, Melita / Kandalaft, Lana E / Speiser, Daniel E / Coukos, George / Harari, Alexandre

Cell reports methods

2023 Volume 3, Issue 4, Page(s) 100459

Abstract: T cell receptor (TCR) technologies, including repertoire analyses and T cell engineering, are increasingly important in the clinical management of cellular immunity in cancer, transplantation, and other immune diseases. However, sensitive and reliable ... ...

Abstract	T cell receptor (TCR) technologies, including repertoire analyses and T cell engineering, are increasingly important in the clinical management of cellular immunity in cancer, transplantation, and other immune diseases. However, sensitive and reliable methods for repertoire analyses and TCR cloning are still lacking. Here, we report on SEQTR, a high-throughput approach to analyze human and mouse repertoires that is more sensitive, reproducible, and accurate as compared with commonly used assays, and thus more reliably captures the complexity of blood and tumor TCR repertoires. We also present a TCR cloning strategy to specifically amplify TCRs from T cell populations. Positioned downstream of single-cell or bulk TCR sequencing, it allows time- and cost-effective discovery, cloning, screening, and engineering of tumor-specific TCRs. Together, these methods will accelerate TCR repertoire analyses in discovery, translational, and clinical settings and permit fast TCR engineering for cellular therapies.
MeSH term(s)	Humans ; Animals ; Mice ; Receptors, Antigen, T-Cell/genetics ; Neoplasms/genetics ; Biological Assay ; Cell Engineering ; Cloning, Molecular
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-04-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2667-2375
ISSN (online)	2667-2375
DOI	10.1016/j.crmeth.2023.100459
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Article ; Online: Activation of the transcription factor NFAT5 in the tumor microenvironment enforces CD8

Tillé, Laure / Cropp, Daniela / Charmoy, Mélanie / Reichenbach, Patrick / Andreatta, Massimo / Wyss, Tania / Bodley, Gabrielle / Crespo, Isaac / Nassiri, Sina / Lourenco, Joao / Leblond, Marine M / Lopez-Rodriguez, Cristina / Speiser, Daniel E / Coukos, George / Irving, Melita / Carmona, Santiago J / Held, Werner / Verdeil, Grégory

Nature immunology

2023 Volume 24, Issue 10, Page(s) 1645–1653

Abstract: Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their ... ...

Abstract	Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. Here we found that NFAT5, an NFAT family transcription factor that lacks an AP-1 docking site, was highly expressed in exhausted CD8
MeSH term(s)	Humans ; Lymphocytic Choriomeningitis ; Transcription Factors/metabolism ; CD8-Positive T-Lymphocytes ; T-Cell Exhaustion ; Persistent Infection ; Tumor Microenvironment ; Programmed Cell Death 1 Receptor/genetics ; Programmed Cell Death 1 Receptor/metabolism ; Lymphocytic choriomeningitis virus ; Neoplasms/metabolism
Chemical Substances	Transcription Factors ; Programmed Cell Death 1 Receptor ; NFAT5 protein, human
Language	English
Publishing date	2023-09-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-023-01614-x
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A cell-based phenotypic library selection and screening approach for the de novo discovery of novel functional chimeric antigen receptors.

Fierle, Julie K / Abram-Saliba, Johan / Atsaves, Vasileios / Brioschi, Matteo / de Tiani, Mariastella / Reichenbach, Patrick / Irving, Melita / Coukos, George / Dunn, Steven M

Scientific reports

2022 Volume 12, Issue 1, Page(s) 1136

Abstract: Anti-tumor therapies that seek to exploit and redirect the cytotoxic killing and effector potential of autologous or syngeneic T cells have shown extraordinary promise and efficacy in certain clinical settings. Such cells, when engineered to express ... ...

Abstract	Anti-tumor therapies that seek to exploit and redirect the cytotoxic killing and effector potential of autologous or syngeneic T cells have shown extraordinary promise and efficacy in certain clinical settings. Such cells, when engineered to express synthetic chimeric antigen receptors (CARs) acquire novel targeting and activation properties which are governed and orchestrated by, typically, antibody fragments specific for a tumor antigen of interest. However, it is becoming increasingly apparent that not all antibodies are equal in this regard, with a growing appreciation that 'optimal' CAR performance requires a consideration of multiple structural and contextual parameters. Thus, antibodies raised by classical approaches and intended for other applications often perform poorly or not at all when repurposed as CARs. With this in mind, we have explored the potential of an in vitro phenotypic CAR library discovery approach that tightly associates antibody-driven bridging of tumor and effector T cells with an informative and functionally relevant CAR activation reporter signal. Critically, we demonstrate the utility of this enrichment methodology for 'real world' de novo discovery by isolating several novel anti-mesothelin CAR-active scFv candidates.
MeSH term(s)	Cell Line, Tumor ; Gene Library ; HEK293 Cells ; Healthy Volunteers ; Humans ; Immunotherapy, Adoptive/methods ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Primary Cell Culture ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/immunology ; Receptors, Chimeric Antigen/isolation & purification ; Single-Chain Antibodies/immunology ; Single-Chain Antibodies/metabolism ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Cytotoxic/metabolism ; T-Lymphocytes, Cytotoxic/transplantation
Chemical Substances	Receptors, Chimeric Antigen ; Single-Chain Antibodies
Language	English
Publishing date	2022-01-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-05058-5
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Article ; Online: Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.

Röhrig, Ute F / Majjigapu, Somi Reddy / Vogel, Pierre / Reynaud, Aline / Pojer, Florence / Dilek, Nahzli / Reichenbach, Patrick / Ascenção, Kelly / Irving, Melita / Coukos, George / Michielin, Olivier / Zoete, Vincent

Journal of enzyme inhibition and medicinal chemistry

2022 Volume 37, Issue 1, Page(s) 1773–1811

Abstract: The haem enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the rate-limiting step in the kynurenine pathway of tryptophan metabolism and plays an essential role in immunity, neuronal function, and ageing. Expression of IDO1 in cancer cells results in ...

Abstract	The haem enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the rate-limiting step in the kynurenine pathway of tryptophan metabolism and plays an essential role in immunity, neuronal function, and ageing. Expression of IDO1 in cancer cells results in the suppression of an immune response, and therefore IDO1 inhibitors have been developed for use in anti-cancer immunotherapy. Here, we report an extension of our previously described highly efficient haem-binding 1,2,3-triazole and 1,2,4-triazole inhibitor series, the best compound having both enzymatic and cellular IC
MeSH term(s)	Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Heme ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; Triazoles/chemistry ; Triazoles/pharmacology
Chemical Substances	Enzyme Inhibitors ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; Triazoles ; Heme (42VZT0U6YR)
Language	English
Publishing date	2022-06-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2082578-X
ISSN	1475-6374 ; 1475-6366
ISSN (online)	1475-6374
ISSN	1475-6366
DOI	10.1080/14756366.2022.2089665
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Zs.A 3004: Show issues

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Article ; Online: VEGFR-2 redirected CAR-T cells are functionally impaired by soluble VEGF-A competition for receptor binding.

Lanitis, Evripidis / Kosti, Paris / Ronet, Catherine / Cribioli, Elisabetta / Rota, Giorgia / Spill, Aodrenn / Reichenbach, Patrick / Zoete, Vincent / Dangaj Laniti, Denarda / Coukos, George / Irving, Melita

Journal for immunotherapy of cancer

2021 Volume 9, Issue 8

Abstract: Background: The adoptive transfer of chimeric antigen receptor (CAR)-T cells has emerged as a potent immunotherapy against some hematological malignancies but not yet for epithelial-derived solid tumors. One critical issue is the paucity of broadly ... ...

Abstract	Background: The adoptive transfer of chimeric antigen receptor (CAR)-T cells has emerged as a potent immunotherapy against some hematological malignancies but not yet for epithelial-derived solid tumors. One critical issue is the paucity of broadly expressed solid tumor antigens (TAs), and another is the presence of suppressive mechanisms in the tumor microenvironment (TME) that can impair CAR-T cell homing, extravasation and effector functions. TAs expressed by endothelial cells of the tumor vasculature are of clinical interest for CAR therapy because of their genomic stability and accessibility to circulating T cells, as well as their expression across multiple tumor types. In this study, we sought to explore limitations to the efficacy of second-generation (2G) murine CAR-T cells redirected against the vascular endothelial growth factor receptor-2 (VEGFR-2) with the well-characterized single-chain variable fragment DC101. Methods: Primary murine T cells were retrovirally transduced to express a 2G anti-VEGFR-2-CAR, and the in vitro binding to VEGFR-2, as well as reactivity against TA-expressing cells, was evaluated in the absence versus presence of exogenous VEGF-A. The CAR-T cells were further tested in vivo for tumor control alone and in combination with anti-VEGF-A antibody. Finally, we performed ex vivo phenotypic analyses of tumor-infiltrating CAR-T cells for the two treatment groups. Results: In line with previous reports, we observed poor control of B16 melanoma by the 2G anti-VEGFR-2 CAR-T cells as a monotherapy. We further showed that VEGFR-2 is not downregulated by B16 melanoma tumors post treatment, but that its soluble ligand VEGF-A is upregulated and furthermore competes in vitro with the CAR-T cells for binding to VEGFR-2. This competition resulted in impaired CAR-T cell adhesion and effector function in vitro that could be restored in the presence of anti-VEGF-A antibody. Finally, we demonstrated that coadministration of anti-VEGF-A antibody in vivo promoted CAR-T cell persistence and tumor control and was associated with reduced frequencies of PD-1 Conclusions: This study represents the first example of impaired function of a vasculature-targeted CAR by an angiogenic ligand and rationalizes the use of combinatorial therapies that target the tumor vasculature and augment CAR-T cell effector function.
MeSH term(s)	Animals ; Humans ; Mice ; Neoplasms/immunology ; Receptors, Chimeric Antigen/genetics ; Vascular Endothelial Growth Factor A/metabolism ; Vascular Endothelial Growth Factor Receptor-2/metabolism
Chemical Substances	Receptors, Chimeric Antigen ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor Receptor-2 (EC 2.7.10.1)
Language	English
Publishing date	2021-08-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2020-002151
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Article ; Online: Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

Röhrig, Ute F / Majjigapu, Somi Reddy / Reynaud, Aline / Pojer, Florence / Dilek, Nahzli / Reichenbach, Patrick / Ascencao, Kelly / Irving, Melita / Coukos, George / Vogel, Pierre / Michielin, Olivier / Zoete, Vincent

Journal of medicinal chemistry

2021 Volume 64, Issue 4, Page(s) 2205–2227

Abstract: The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different ... ...

Abstract	The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds.
MeSH term(s)	Azoles/chemical synthesis ; Azoles/metabolism ; Azoles/pharmacology ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/pharmacology ; HEK293 Cells ; Humans ; Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Molecular Dynamics Simulation ; Molecular Structure ; Protein Binding ; Quantitative Structure-Activity Relationship
Chemical Substances	Azoles ; Enzyme Inhibitors ; IDO1 protein, human ; Indoleamine-Pyrrole 2,3,-Dioxygenase
Language	English
Publishing date	2021-02-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.0c01968
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Zs.B 151: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article: The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase

Redon, Sophie / Reichenbach, Patrick / Lingner, Joachim

Nucleic acids research. 2010 Sept., v. 38, no. 17

2010

Abstract: Telomeres, the physical ends of eukaryotes chromosomes are transcribed into telomeric repeat containing RNA (TERRA), a large non-coding RNA of unknown function, which forms an integral part of telomeric heterochromatin. TERRA molecules resemble in ... ...

Abstract	Telomeres, the physical ends of eukaryotes chromosomes are transcribed into telomeric repeat containing RNA (TERRA), a large non-coding RNA of unknown function, which forms an integral part of telomeric heterochromatin. TERRA molecules resemble in sequence the telomeric DNA substrate as they contain 5'-UUAGGG-3' repeats near their 3'-end which are complementary to the template sequence of telomerase RNA. Here we demonstrate that endogenous TERRA is bound to human telomerase in cell extracts. Using in vitro reconstituted telomerase and synthetic TERRA molecules we demonstrate that the 5'-UUAGGG-3' repeats of TERRA base pair with the RNA template of the telomerase RNA moiety (TR). In addition TERRA contacts the telomerase reverse transcriptase (TERT) protein subunit independently of hTR. In vitro studies further demonstrate that TERRA is not used as a telomerase substrate. Instead, TERRA acts as a potent competitive inhibitor for telomeric DNA in addition to exerting an uncompetitive mode of inhibition. Our data identify TERRA as a telomerase ligand and natural direct inhibitor of human telomerase. Telomerase regulation by the telomere substrate may be mediated via its transcription.
Keywords	DNA ; chemical elements ; eukaryotic cells ; heterochromatin ; humans ; in vitro studies ; ligands ; non-coding RNA ; protein subunits ; telomerase ; telomeres ; transcription (genetics)
Language	English
Dates of publication	2010-09
Size	p. 5797-5806.
Document type	Article
ZDB-ID	186809-3
ISSN	0301-5610 ; 0305-1048
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkq296
Database	NAL-Catalogue (AGRICOLA)

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Z 79/704: Show issues

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Article ; Online: Molecular dissection of telomeric repeat-containing RNA biogenesis unveils the presence of distinct and multiple regulatory pathways.

Porro, Antonio / Feuerhahn, Sascha / Reichenbach, Patrick / Lingner, Joachim

Molecular and cellular biology

2010 Volume 30, Issue 20, Page(s) 4808–4817

Abstract: Telomeres are transcribed into telomeric repeat-containing RNA (TERRA), large, heterogeneous, noncoding transcripts which form part of the telomeric heterochromatin. Despite a large number of functions that have been ascribed to TERRA, little is known ... ...

Abstract	Telomeres are transcribed into telomeric repeat-containing RNA (TERRA), large, heterogeneous, noncoding transcripts which form part of the telomeric heterochromatin. Despite a large number of functions that have been ascribed to TERRA, little is known about its biogenesis. Here, we present the first comprehensive analysis of the molecular structure of TERRA. We identify biochemically distinct TERRA complexes, and we describe TERRA regulation during the cell cycle. Moreover, we demonstrate that TERRA 5' ends contain 7-methylguanosine cap structures and that the poly(A) tail, present on a fraction of TERRA transcripts, contributes to their stability. Poly(A)(-) TERRA, but not poly(A)(+) TERRA, is associated with chromatin, possibly reflecting distinct biological roles of TERRA ribonucleoprotein complexes. In support of this idea, poly(A)(-) and poly(A)(+) TERRA molecules end with distinct sequence registers. We also determine that the bulk of 3'-terminal UUAGGG repeats have an average length of 200 bases, indicating that the length heterogeneity of TERRA likely stems from its subtelomeric regions. Finally, we find that TERRA is regulated during the cell cycle, being lowest in late S phase and peaking in early G(1). Our analyses offer the basis for investigating multiple regulatory pathways that affect TERRA synthesis, processing, turnover, and function.
MeSH term(s)	Base Sequence ; Cell Cycle ; Cell Line ; HeLa Cells ; Humans ; RNA/biosynthesis ; RNA/genetics ; RNA Caps/metabolism ; RNA Processing, Post-Transcriptional ; RNA Stability ; RNA, Messenger/metabolism ; Subcellular Fractions/metabolism ; Tandem Repeat Sequences ; Telomere/genetics ; Telomere/metabolism
Chemical Substances	RNA Caps ; RNA, Messenger ; RNA (63231-63-0)
Language	English
Publishing date	2010-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00460-10
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Zs.A 1666: Show issues

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Article ; Online: The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase.

Redon, Sophie / Reichenbach, Patrick / Lingner, Joachim

Nucleic acids research

2010 Volume 38, Issue 17, Page(s) 5797–5806

Abstract	Telomeres, the physical ends of eukaryotes chromosomes are transcribed into telomeric repeat containing RNA (TERRA), a large non-coding RNA of unknown function, which forms an integral part of telomeric heterochromatin. TERRA molecules resemble in sequence the telomeric DNA substrate as they contain 5'-UUAGGG-3' repeats near their 3'-end which are complementary to the template sequence of telomerase RNA. Here we demonstrate that endogenous TERRA is bound to human telomerase in cell extracts. Using in vitro reconstituted telomerase and synthetic TERRA molecules we demonstrate that the 5'-UUAGGG-3' repeats of TERRA base pair with the RNA template of the telomerase RNA moiety (TR). In addition TERRA contacts the telomerase reverse transcriptase (TERT) protein subunit independently of hTR. In vitro studies further demonstrate that TERRA is not used as a telomerase substrate. Instead, TERRA acts as a potent competitive inhibitor for telomeric DNA in addition to exerting an uncompetitive mode of inhibition. Our data identify TERRA as a telomerase ligand and natural direct inhibitor of human telomerase. Telomerase regulation by the telomere substrate may be mediated via its transcription.
MeSH term(s)	Cell Line ; Cell Nucleus/enzymology ; Humans ; Ligands ; Peptides/metabolism ; RNA, Untranslated/chemistry ; RNA, Untranslated/metabolism ; Repetitive Sequences, Nucleic Acid ; Telomerase/antagonists & inhibitors ; Telomerase/chemistry ; Telomerase/metabolism ; Telomere/chemistry ; Templates, Genetic
Chemical Substances	Ligands ; Peptides ; RNA, Untranslated ; TERT protein, human (EC 2.7.7.49) ; Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2010-05-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkq296
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