UMR3244 – Dynamique de l’information génétique

Publications de l’équipe

Année de publication : 2013

Sara Jaber, Iva Simeonova, Franck Toledo (2013 Dec 21)

[Moderation in all things: p53 deregulation, cancer and telomere syndromes].

Médecine sciences : M/S : 1071-3 : DOI : 10.1051/medsci/20132912003 En savoir plus
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Guilhem Faure, Patrick Revy, Michael Schertzer, Arturo Londono-Vallejo, Isabelle Callebaut (2013 Oct 17)

The C-terminal extension of human RTEL1, mutated in Hoyeraal-Hreidarsson syndrome, contains harmonin-N-like domains.

Proteins : 897-903 : DOI : 10.1002/prot.24438 En savoir plus
Résumé

Several studies have recently shown that germline mutations in RTEL1, an essential DNA helicase involved in telomere regulation and DNA repair, cause Hoyeraal-Hreidarsson syndrome (HHS), a severe form of dyskeratosis congenita. Using original new softwares, facilitating the delineation of the different domains of the protein and the identification of remote relationships for orphan domains, we outline here that the C-terminal extension of RTEL1, downstream of its catalytic domain and including several HHS-associated mutations, contains a yet unidentified tandem of harmonin-N-like domains, which may serve as a hub for partner interaction. This finding highlights the potential critical role of this region for the function of RTEL1 and gives insights into the impact that the identified mutations would have on the structure and function of these domains.

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Antonin Morillon, Jean-Christophe Andrau (2013 Sep 10)

Editorial for « Diversity of the non-coding transcriptomes revealed by RNA-seq technologies ».

Methods (San Diego, Calif.) : 1-2 : DOI : 10.1016/j.ymeth.2013.08.030 En savoir plus
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Zhong Deng, Galina Glousker, Aliah Molczan, Alan J Fox, Noa Lamm, Jayaraju Dheekollu, Orr-El Weizman, Michael Schertzer, Zhuo Wang, Olga Vladimirova, Jonathan Schug, Memet Aker, Arturo Londoño-Vallejo, Klaus H Kaestner, Paul M Lieberman, Yehuda Tzfati (2013 Aug 21)

Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome.

Proceedings of the National Academy of Sciences of the United States of America : E3408-16 : DOI : 10.1073/pnas.1300600110 En savoir plus
Résumé

Telomeres repress the DNA damage response at the natural chromosome ends to prevent cell-cycle arrest and maintain genome stability. Telomeres are elongated by telomerase in a tightly regulated manner to ensure a sufficient number of cell divisions throughout life, yet prevent unlimited cell division and cancer development. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and a broad range of pathologies, including bone marrow failure, immunodeficiency, and developmental defects. HHS-causing mutations have previously been found in telomerase and the shelterin component telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2 (TIN2). We identified by whole-genome exome sequencing compound heterozygous mutations in four siblings affected with HHS, in the gene encoding the regulator of telomere elongation helicase 1 (RTEL1). Rtel1 was identified in mouse by its genetic association with telomere length. However, its mechanism of action and whether it regulates telomere length in human remained unknown. Lymphoblastoid cell lines obtained from a patient and from the healthy parents carrying heterozygous RTEL1 mutations displayed telomere shortening, fragility and fusion, and growth defects in culture. Ectopic expression of WT RTEL1 suppressed the telomere shortening and growth defect, confirming the causal role of the RTEL1 mutations in HHS and demonstrating the essential function of human RTEL1 in telomere protection and elongation. Finally, we show that human RTEL1 interacts with the shelterin protein TRF1, providing a potential recruitment mechanism of RTEL1 to telomeres.

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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
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Jesús A Carballo, Silvia Panizza, Maria Elisabetta Serrentino, Anthony L Johnson, Marco Geymonat, Valérie Borde, Franz Klein, Rita S Cha (2013 Jul 5)

Budding yeast ATM/ATR control meiotic double-strand break (DSB) levels by down-regulating Rec114, an essential component of the DSB-machinery.

PLoS genetics : e1003545 : DOI : 10.1371/journal.pgen.1003545 En savoir plus
Résumé

An essential feature of meiosis is Spo11 catalysis of programmed DNA double strand breaks (DSBs). Evidence suggests that the number of DSBs generated per meiosis is genetically determined and that this ability to maintain a pre-determined DSB level, or « DSB homeostasis », might be a property of the meiotic program. Here, we present direct evidence that Rec114, an evolutionarily conserved essential component of the meiotic DSB-machinery, interacts with DSB hotspot DNA, and that Tel1 and Mec1, the budding yeast ATM and ATR, respectively, down-regulate Rec114 upon meiotic DSB formation through phosphorylation. Mimicking constitutive phosphorylation reduces the interaction between Rec114 and DSB hotspot DNA, resulting in a reduction and/or delay in DSB formation. Conversely, a non-phosphorylatable rec114 allele confers a genome-wide increase in both DSB levels and in the interaction between Rec114 and the DSB hotspot DNA. These observations strongly suggest that Tel1 and/or Mec1 phosphorylation of Rec114 following Spo11 catalysis down-regulates DSB formation by limiting the interaction between Rec114 and DSB hotspots. We also present evidence that Ndt80, a meiosis specific transcription factor, contributes to Rec114 degradation, consistent with its requirement for complete cessation of DSB formation. Loss of Rec114 foci from chromatin is associated with homolog synapsis but independent of Ndt80 or Tel1/Mec1 phosphorylation. Taken together, we present evidence for three independent ways of regulating Rec114 activity, which likely contribute to meiotic DSBs-homeostasis in maintaining genetically determined levels of breaks.

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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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Maria-Elisabetta Serrentino, Emmanuel Chaplais, Vérane Sommermeyer, Valérie Borde (2013 Apr 9)

Differential association of the conserved SUMO ligase Zip3 with meiotic double-strand break sites reveals regional variations in the outcome of meiotic recombination.

PLoS genetics : e1003416 : DOI : 10.1371/journal.pgen.1003416 En savoir plus
Résumé

During the first meiotic prophase, programmed DNA double-strand breaks (DSBs) are distributed non randomly at hotspots along chromosomes, to initiate recombination. In all organisms, more DSBs are formed than crossovers (CO), the repair product that creates a physical link between homologs and allows their correct segregation. It is not known whether all DSB hotspots are also CO hotspots or if the CO/DSB ratio varies with the chromosomal location. Here, we investigated the variations in the CO/DSB ratio by mapping genome-wide the binding sites of the Zip3 protein during budding yeast meiosis. We show that Zip3 associates with DSB sites that are engaged in repair by CO, and Zip3 enrichment at DSBs reflects the DSB tendency to be repaired by CO. Moreover, the relative amount of Zip3 per DSB varies with the chromosomal location, and specific chromosomal features are associated with high or low Zip3 per DSB. This work shows that DSB hotspots are not necessarily CO hotspots and suggests that different categories of DSB sites may fulfill different functions.

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Valérie Borde, Bernard de Massy (2013 Apr 2)

Programmed induction of DNA double strand breaks during meiosis: setting up communication between DNA and the chromosome structure.

Current opinion in genetics & development : 147-55 : DOI : 10.1016/j.gde.2012.12.002 En savoir plus
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During the first meiotic prophase, hundreds of DNA double strand breaks (DSBs) are deliberately self-inflicted along chromosomes in order to promote homologous recombination between homologs. These DSBs, catalyzed by the evolutionary conserved Spo11 protein, are highly regulated. Recent studies in yeast and mammals have identified key components involved in meiotic DSB formation. In mammals, the DNA binding specificity of PRDM9 determines where DSB occur, whereas in yeast, Spo11 acts in regions which one important feature is chromatin accessibility. However, DSB formation requires additional proteins located on chromosome axes, and the Saccharomyces cerevisiae protein, Spp1 has been recently identified to make the link between axes and DSB sites. These recent findings open exciting routes to understanding how the requirement to regulate DSBs along and between homologs is achieved.

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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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Aurélie Morin, Boris Bardot, Iva Simeonova, Vincent Lejour, Rachida Bouarich-Bourimi, Franck Toledo (2013 Feb 16)

Of mice and men: fuzzy tandem repeats and divergent p53 transcriptional repertoires.

Transcription : 67-71 : DOI : 10.4161/trns.23772 En savoir plus
Résumé

The clinical importance of tumor suppressor p53 makes it one of the most studied transcription factors. A comparison of mammalian p53 transcriptional repertoires may help identify fundamental principles in genome evolution and better understand cancer processes. Here we summarize mechanisms underlying the divergence of mammalian p53 transcriptional repertoires, with an emphasis on the rapid evolution of fuzzy tandem repeats containing p53 response elements.

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