Télomères et Cancer

Publications de l’équipe

Année de publication : 2013

Sylvain Marchand-Adam, Bruno Diot, Pascal Magro, Anne De Muret, Christophe Guignabert, Caroline Kannengiesser, Arturo Londono-Vallejo, Irena Draskovic, Annick Toutain, Patrice Diot (2013 Aug 3)

Pulmonary alveolar proteinosis revealing a telomerase disease.

American journal of respiratory and critical care medicine : 402-4 : DOI : 10.1164/rccm.201301-0010LE En savoir plus
Résumé

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Annamaria Biroccio, Julien Cherfils-Vicini, Adeline Augereau, Sébastien Pinte, Serge Bauwens, Jing Ye, Thomas Simonet, Béatrice Horard, Karine Jamet, Ludovic Cervera, Aaron Mendez-Bermudez, Delphine Poncet, Renée Grataroli, Claire T'kint de Rodenbeeke, Erica Salvati, Angela Rizzo, Pasquale Zizza, Michelle Ricoul, Céline Cognet, Thomas Kuilman, Helene Duret, Florian Lépinasse, Jacqueline Marvel, Els Verhoeyen, François-Loïc Cosset, Daniel Peeper, Mark J Smyth, Arturo Londoño-Vallejo, Laure Sabatier, Vincent Picco, Gilles Pages, Jean-Yves Scoazec, Antonella Stoppacciaro, Carlo Leonetti, Eric Vivier, Eric Gilson (2013 Jun 25)

TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells.

Nature cell biology : 818-28 : DOI : 10.1038/ncb2774 En savoir plus
Résumé

Dysfunctional telomeres suppress tumour progression by activating cell-intrinsic programs that lead to growth arrest. Increased levels of TRF2, a key factor in telomere protection, are observed in various human malignancies and contribute to oncogenesis. We demonstrate here that a high level of TRF2 in tumour cells decreased their ability to recruit and activate natural killer (NK) cells. Conversely, a reduced dose of TRF2 enabled tumour cells to be more easily eliminated by NK cells. Consistent with these results, a progressive upregulation of TRF2 correlated with decreased NK cell density during the early development of human colon cancer. By screening for TRF2-bound genes, we found that HS3ST4–a gene encoding for the heparan sulphate (glucosamine) 3-O-sulphotransferase 4–was regulated by TRF2 and inhibited the recruitment of NK cells in an epistatic relationship with TRF2. Overall, these results reveal a TRF2-dependent pathway that is tumour-cell extrinsic and regulates NK cell immunity.

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Clara Lopes Novo, Catherine Polese, Nicolas Matheus, Anabelle Decottignies, Arturo Londono-Vallejo, Vincent Castronovo, Denis Mottet (2013 Jun 5)

A new role for histone deacetylase 5 in the maintenance of long telomeres.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology : 3632-42 : DOI : 10.1096/fj.12-224204 En savoir plus
Résumé

Telomeres are major regulators of genome stability and cell proliferation. A detailed understanding of the mechanisms involved in their maintenance is of foremost importance. Of those, telomere chromatin remodeling is probably the least studied; thus, we intended to explore the role of a specific histone deacetylase on telomere maintenance. We uncovered a new role for histone deacetylase 5 (HDAC5) in telomere biology. We report that HDAC5 is recruited to the long telomeres of osteosarcoma- and fibrosarcoma-derived cell lines, where it ensures proper maintenance of these repetitive regions. Indeed, depletion of HDAC5 by RNAi resulted in the shortening of longer telomeres and homogenization of telomere length in cells that use either telomerase or an alternative mechanism of telomere maintenance. Furthermore, we present evidence for the activation of telomere recombination on depletion of HDAC5 in fibrosarcoma telomerase-positive cancer cells. Of potential importance, we also found that depletion of HDAC5 sensitizes cancer cells with long telomeres to chemotherapeutic drugs. Cells with shorter telomeres were used to control the specificity of HDAC5 role in the maintenance of long telomeres. HDAC5 is essential for the length maintenance of long telomeres and its depletion is required for sensitization of cancer cells with long telomeres to chemotherapy.

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Dennis Kappei, Falk Butter, Christian Benda, Marion Scheibe, Irena Draškovič, Michelle Stevense, Clara Lopes Novo, Claire Basquin, Masatake Araki, Kimi Araki, Dragomir Blazhev Krastev, Ralf Kittler, Rolf Jessberger, J Arturo Londoño-Vallejo, Matthias Mann, Frank Buchholz (2013 May 21)

HOT1 is a mammalian direct telomere repeat-binding protein contributing to telomerase recruitment.

The EMBO journal : 1681-701 : DOI : 10.1038/emboj.2013.105 En savoir plus
Résumé

Telomeres are repetitive DNA structures that, together with the shelterin and the CST complex, protect the ends of chromosomes. Telomere shortening is mitigated in stem and cancer cells through the de novo addition of telomeric repeats by telomerase. Telomere elongation requires the delivery of the telomerase complex to telomeres through a not yet fully understood mechanism. Factors promoting telomerase-telomere interaction are expected to directly bind telomeres and physically interact with the telomerase complex. In search for such a factor we carried out a SILAC-based DNA-protein interaction screen and identified HMBOX1, hereafter referred to as homeobox telomere-binding protein 1 (HOT1). HOT1 directly and specifically binds double-stranded telomere repeats, with the in vivo association correlating with binding to actively processed telomeres. Depletion and overexpression experiments classify HOT1 as a positive regulator of telomere length. Furthermore, immunoprecipitation and cell fractionation analyses show that HOT1 associates with the active telomerase complex and promotes chromatin association of telomerase. Collectively, these findings suggest that HOT1 supports telomerase-dependent telomere elongation.

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Simona Nanni, Aurora Aiello, Agnese Re, Alessandro Guffanti, Valentina Benvenuti, Claudia Colussi, Luis Jaime Castro-Vega, Armando Felsani, Arturo Londono-Vallejo, Maurizio C Capogrossi, Silvia Bacchetti, Carlo Gaetano, Alfredo Pontecorvi, Antonella Farsetti (2013 May 10)

Estrogen-dependent dynamic profile of eNOS-DNA associations in prostate cancer.

PloS one : e62522 : DOI : 10.1371/journal.pone.0062522 En savoir plus
Résumé

In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa.

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Tangui Le Guen, Laurent Jullien, Fabien Touzot, Michael Schertzer, Laetitia Gaillard, Mylène Perderiset, Wassila Carpentier, Patrick Nitschke, Capucine Picard, Gérard Couillault, Jean Soulier, Alain Fischer, Isabelle Callebaut, Nada Jabado, Arturo Londono-Vallejo, Jean-Pierre de Villartay, Patrick Revy (2013 Apr 18)

Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability.

Human molecular genetics : 3239-49 : DOI : 10.1093/hmg/ddt178 En savoir plus
Résumé

Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrow failure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomere dysfunction and these diseases. By combining whole-genome linkage analysis and exome sequencing, we identified compound heterozygous RTEL1 (regulator of telomere elongation helicase 1) mutations in three patients with HHS from two unrelated families. RTEL1 is a DNA helicase that participates in DNA replication, DNA repair and telomere integrity. We show that, in addition to short telomeres, RTEL1-deficient cells from patients exhibit hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges and telomeric aberrations. Collectively, these results identify RTEL1 as a novel HHS-causing gene and highlight its role as a genomic caretaker in humans.

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Clara Novo, Nausica Arnoult, Win-Yan Bordes, Luis Castro-Vega, Anne Gibaud, Bernard Dutrillaux, Silvia Bacchetti, Arturo Londoño-Vallejo (2013 Mar 23)

The heterochromatic chromosome caps in great apes impact telomere metabolism.

Nucleic acids research : 4792-801 : DOI : 10.1093/nar/gkt169 En savoir plus
Résumé

In contrast with the limited sequence divergence accumulated after separation of higher primate lineages, marked cytogenetic variation has been associated with the genome evolution in these species. Studying the impact of such structural variations on defined molecular processes can provide valuable insights on how genome structural organization contributes to organismal evolution. Here, we show that telomeres on chromosome arms carrying subtelomeric heterochromatic caps in the chimpanzee, which are completely absent in humans, replicate later than telomeres on chromosome arms without caps. In gorilla, on the other hand, a proportion of the subtelomeric heterochromatic caps present in most chromosome arms are associated with large blocks of telomere-like sequences that follow a replication program different from that of bona fide telomeres. Strikingly, telomere-containing RNA accumulates extrachromosomally in gorilla mitotic cells, suggesting that at least some aspects of telomere-containing RNA biogenesis have diverged in gorilla, perhaps in concert with the evolution of heterochromatic caps in this species.

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Luis Jaime Castro-Vega, Karina Jouravleva, Win-Yan Liu, Carolina Martinez, Pierre Gestraud, Philippe Hupé, Nicolas Servant, Benoît Albaud, David Gentien, Sophie Gad, Stéphane Richard, Silvia Bacchetti, Arturo Londoño-Vallejo (2013 Jan 30)

Telomere crisis in kidney epithelial cells promotes the acquisition of a microRNA signature retrieved in aggressive renal cell carcinomas.

Carcinogenesis : 1173-80 : DOI : 10.1093/carcin/bgt029 En savoir plus
Résumé

Telomere shortening is a major source of chromosome instability (CIN) at early stages during carcinogenesis. However, the mechanisms through which telomere-driven CIN (T-CIN) contributes to the acquisition of tumor phenotypes remain uncharacterized. We discovered that human epithelial kidney cells undergoing T-CIN display massive microRNA (miR) expression changes that are not related to local losses or gains. This widespread miR deregulation encompasses a miR-200-dependent epithelial-to-mesenchymal transition (EMT) that confers to immortalized pre-tumoral cells phenotypic traits of metastatic potential. Remarkably, a miR signature of these cells, comprising a downregulation of miRs with conserved expression in kidney, was retrieved in poorly differentiated aggressive renal cell carcinomas. Our results reveal an unanticipated connection between telomere crisis and the activation of the EMT program that occurs at pre-invasive stages of epithelial cancers, through mechanisms that involve miR deregulation. Thus, this study provides a new rational into how telomere instability contributes to the acquisition of the malignant phenotype.

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Irena Draskovic, Arturo Londono Vallejo (2013 Jan 2)

Telomere recombination and alternative telomere lengthening mechanisms.

Frontiers in bioscience (Landmark edition) : 1-20 En savoir plus
Résumé

Telomeres are nucleoprotein structures at the ends of linear chromosomes that protect them from being recognized as DNA double stranded breaks. Telomeres shorten with every cell division and in the absence of the checkpoint mechanisms critical telomere shortening leads to chromosome end fusions and genomic instability. Cancer cells achieve immortality by engaging in one of the two known mechanisms for telomere maintenance: elongation by telomerase or through recombination. Recombination based elongation of telomeres, also known as alternative lengthening of telomeres or ALT, is prevalent among cancers of mesenchymal origin. However, the conditions favoring ALT emergence are not known. Here we will discuss possible players in ALT mechanisms, including recruitment of telomeres to recombination centers, alterations of telomere associated proteins and modifications at the level of chromatin that could generate recombination permissive conditions at telomeres.

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Année de publication : 2012

D C Silvestre, A Londoño-Vallejo (2012 Jul 5)

Telomere dynamics in mammals.

Genome dynamics : 29-45 : DOI : 10.1159/000337128 En savoir plus
Résumé

Telomeres are specialized structures found at the end of linear chromosomes. Telomere structure and functions are conserved throughout evolution and are essential for genome stability, preventing chromosome ends from being recognized as damaged DNA and from being fused or degraded by the DNA repair machinery. The structure of telomeres is intrinsically dynamic and affected by multiple processes that impact their length and nucleoprotein composition, thus leading to functional and structural heterogeneity. We review here the most significant facets of telomere metabolism and its dynamics, with an emphasis on human biology.

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J Arturo Londoño-Vallejo, Raymund J Wellinger (2012 Jun 26)

Telomeres and telomerase dance to the rhythm of the cell cycle.

Trends in biochemical sciences : 391-9 : DOI : 10.1016/j.tibs.2012.05.004 En savoir plus
Résumé

The stability of the ends of linear eukaryotic chromosomes is ensured by functional telomeres, which are composed of short, species-specific direct repeat sequences. The maintenance of telomeres depends on a specialized ribonucleoprotein (RNP) called telomerase. Both telomeres and telomerase are dynamic entities with different physical behaviors and, given their substrate-enzyme relation, they must establish a productive interaction. Regulatory mechanisms controlling this interaction are key missing elements in our understanding of telomere functions. Here, we review the dynamic properties of telomeres and the maturing telomerase RNPs, and summarize how tracking the timing of their dance during the cell cycle will yield insights into chromosome stability mechanisms. Cancer cells often display loss of genome integrity; therefore, these issues are of particular interest for our understanding of cancer initiation or progression.

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Clara Lopes Novo, J Arturo Londoño-Vallejo (2012 Feb 15)

Telomeres and the nucleus.

Seminars in cancer biology : 116-24 : DOI : 10.1016/j.semcancer.2012.02.001 En savoir plus
Résumé

Telomeres are crucial for the maintenance of genome stability through « capping » of chromosome ends to prevent their recognition as double-strand breaks, thus avoiding end-to-end fusions or illegitimate recombination [1-3]. Similar to other genomic regions, telomeres participate to the nuclear architecture while being highly mobile. The interaction of telomeres with nuclear domains or compartments greatly differs not only between organisms but also between cells within the same organism. It is also expected that biological processes like replication, repair or telomere elongation impact the distribution of chromosome extremities within the nucleus, as they probably do with other regions of the genome. Pathological processes such as cancer induce profound changes in the nuclear architecture, which also affects telomere dynamics and spatial organization. Here we will expose our present knowledge on the relationship between telomeres and nuclear architecture and on how this relationship is affected by normal or abnormal telomere metabolisms.

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Année de publication : 2011

Isabelle Ourliac-Garnier, Arturo Londoño-Vallejo (2011 Apr 5)

Telomere strand-specific length analysis by fluorescent in situ hybridization (Q-CO-FISH).

Methods in molecular biology (Clifton, N.J.) : 33-46 : DOI : 10.1007/978-1-61779-092-8_4 En savoir plus
Résumé

The implementation of quantitative approaches in telomere chromosome-oriented FISH (telomeric CO-FISH) allows the assessment of the relative efficiency of lagging versus leading strand telomere replication and thus provides information on the implicated mechanisms. Here, we describe a simple method for telomere strand-specific analyses and discuss its potential applications.

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Isabelle Ourliac-Garnier, Arturo Londoño-Vallejo (2011 Apr 5)

Telomere length analysis by quantitative fluorescent in situ hybridization (Q-FISH).

Methods in molecular biology (Clifton, N.J.) : 21-31 : DOI : 10.1007/978-1-61779-092-8_3 En savoir plus
Résumé

Length is a functional parameter of telomeres, the nucleoprotein structures that protect chromosome ends. The availability of highly specific, high-affinity probes for telomeric repeated sequences allowed the development of quantitative approaches aimed at measuring telomere length directly on chromosomes or in interphase nuclei. Here, we describe a general method for telomere quantitative FISH on metaphase chromosomes and discuss its most common applications in research.

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Année de publication : 2010

N S Zhdanova, Iu M Minina, T V Karamysheva, N B Rubtsov, J-A Londono-Vallejo (2010 Nov 11)

[The structure of long telomeres in chromosomes of the Iberian shrew].

Genetika : 1222-5 En savoir plus
Résumé

It is shown that the size, localization, and structure of telomeres in the Iberian shrew (Sorex granarius) are not characteristic of mammals. In this species, long telomeres of an average size of 213 kb are localized on the short arms of all 32 acrocentrics; ribosomal blocks and active nucleolus-organizing regions (NORs) were also discovered there. At the remaining chromosome ends the average size of telomeres is 3.8 kb. However, in a closely related species, Sorex araneus, all telomeres have size similar to that of human telomeres, i.e., 6.8-15.2 kb. Despite the fact that some long telomeres contain ribosomal repeats in addition to telomeric ones, the long telomeres have preserved asymmetry of G- and C-rich strands as in functional telomeres. It is probable that long telomeres were formed in meiosis at the stage of chromosome bouquet as a result of global reorganization of the chromosome ends. The provoking factors for such reorganization might be the fission of several metacentrics and the necessity of telomerization of the resulting acrocentrics.

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