UMR3244 – Dynamique de l’information génétique

Publications de l’équipe

Année de publication : 2013

Iva Simeonova, Sara Jaber, Irena Draskovic, Boris Bardot, Ming Fang, Rachida Bouarich-Bourimi, Vincent Lejour, Laure Charbonnier, Claire Soudais, Jean-Christophe Bourdon, Michel Huerre, Arturo Londono-Vallejo, Franck Toledo (2013 Feb 15)

Mutant mice lacking the p53 C-terminal domain model telomere syndromes.

Cell reports : 2046-58 : DOI : 10.1016/j.celrep.2013.05.028 En savoir plus
Résumé

Mutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53Δ31, a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres. Indeed, p53Δ31/Δ31 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Heterozygous p53+/Δ31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms. Importantly, several genes involved in telomere metabolism were downregulated in p53Δ31/Δ31 cells, including Dyskerin, Rtel1, and Tinf2, which are mutated in dyskeratosis congenita, and Terf1, which is implicated in aplastic anemia. Together, these data reveal that a truncating mutation can activate p53 and that p53 plays a major role in the regulation of telomere metabolism.

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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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Céline Vallot, Christophe Huret, Yann Lesecque, Alissa Resch, Noufissa Oudrhiri, Annelise Bennaceur-Griscelli, Laurent Duret, Claire Rougeulle (2013 Jan 22)

XACT, a long noncoding transcript coating the active X chromosome in human pluripotent cells.

Nature genetics : 239-41 : DOI : 10.1038/ng.2530 En savoir plus
Résumé

X-chromosome inactivation (XCI) in mammals relies on XIST, a long noncoding transcript that coats and silences the X chromosome in cis. Here we report the discovery of a long noncoding RNA, XACT, that is expressed from and coats the active X chromosome specifically in human pluripotent cells. In the absence of XIST, XACT is expressed from both X chromosomes in humans but not in mice, suggesting a unique role for XACT in the control of human XCI initiation.

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Vérane Sommermeyer, Claire Béneut, Emmanuel Chaplais, Maria Elisabetta Serrentino, Valérie Borde (2013 Jan 10)

Spp1, a member of the Set1 Complex, promotes meiotic DSB formation in promoters by tethering histone H3K4 methylation sites to chromosome axes.

Molecular cell : 43-54 : DOI : 10.1016/j.molcel.2012.11.008 En savoir plus
Résumé

Meiotic chromosomes are organized into arrays of loops that are anchored to the chromosome axis structure. Programmed DNA double-strand breaks (DSBs) that initiate meiotic recombination, catalyzed by Spo11 and accessory DSB proteins, form in loop sequences in promoters, whereas the DSB proteins are located on chromosome axes. Mechanisms bridging these two chromosomal regions for DSB formation have remained elusive. Here we show that Spp1, a conserved member of the histone H3K4 methyltransferase Set1 complex, is required for normal levels of DSB formation and is associated with chromosome axes during meiosis, where it physically interacts with the Mer2 DSB protein. The PHD finger module of Spp1, which reads H3K4 methylation close to promoters, promotes DSB formation by tethering these regions to chromosome axes and activating cleavage by the DSB proteins. This paper provides the molecular mechanism linking DSB sequences to chromosome axes and explains why H3K4 methylation is important for meiotic recombination.

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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

Iva Simeonova, Vincent Lejour, Boris Bardot, Rachida Bouarich-Bourimi, Aurélie Morin, Ming Fang, Laure Charbonnier, Franck Toledo (2012 Nov 23)

Fuzzy tandem repeats containing p53 response elements may define species-specific p53 target genes.

PLoS genetics : e1002731 : DOI : 10.1371/journal.pgen.1002731 En savoir plus
Résumé

Evolutionary forces that shape regulatory networks remain poorly understood. In mammals, the Rb pathway is a classic example of species-specific gene regulation, as a germline mutation in one Rb allele promotes retinoblastoma in humans, but not in mice. Here we show that p53 transactivates the Retinoblastoma-like 2 (Rbl2) gene to produce p130 in murine, but not human, cells. We found intronic fuzzy tandem repeats containing perfect p53 response elements to be important for this regulation. We next identified two other murine genes regulated by p53 via fuzzy tandem repeats: Ncoa1 and Klhl26. The repeats are poorly conserved in evolution, and the p53-dependent regulation of the murine genes is lost in humans. Our results indicate a role for the rapid evolution of tandem repeats in shaping differences in p53 regulatory networks between mammalian species.

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Année de publication : 2013

Maxime Wery, Marc Descrimes, Claude Thermes, Daniel Gautheret, Antonin Morillon (2012 Sep 18)

Zinc-mediated RNA fragmentation allows robust transcript reassembly upon whole transcriptome RNA-Seq.

Methods (San Diego, Calif.) : 25-31 : DOI : 10.1016/j.ymeth.2013.03.009 En savoir plus
Résumé

Whole transcriptome RNA-Seq has emerged as a powerful tool in transcriptomics, enabling genome-wide quantitative analysis of gene expression and qualitative identification of novel coding or non-coding RNA species through transcriptome reassembly. Common protocols for preparation of RNA-Seq libraries include an RNA fragmentation step for which several RNA sizing techniques are commercially available. To date, there is no global information about their putative bias on transcriptome analysis. Here we compared the effects of RNase III- and zinc-mediated RNA fragmentation on transcript expression measurement and transcriptome reassembly in the budding yeast Saccharomyces cerevisiae. We observed that RNA cleavage by RNase III is heterogeneous along transcripts with a striking decrease of autocorrelation between adjacent nucleotides along the transcriptome. This had little impact on mRNA expression measurement, but specific classes of transcripts such as abundant non-coding RNAs were underrepresented in the libraries constructed using RNase III. Furthermore, zinc-mediated fragmentation allows proper reassembly of more transcripts, with more precise 5′ and 3′ ends. Together, our results show that transcriptome reassembly from RNA-Seq data is very sensitive to the RNA fragmentation technique, and that zinc-mediated fragmentation provides more robust and accurate transcript identification than cleavage by RNase III.

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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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Maria-Elisabetta Serrentino, Valérie Borde (2012 Apr 11)

The spatial regulation of meiotic recombination hotspots: are all DSB hotspots crossover hotspots?

Experimental cell research : 1347-52 : DOI : 10.1016/j.yexcr.2012.03.025 En savoir plus
Résumé

A key step for the success of meiosis is programmed homologous recombination, during which crossovers, or exchange of chromosome arms, take place. Crossovers increase genetic diversity but their main function is to ensure accurate chromosome segregation. Defects in crossover number and position produce aneuploidies that represent the main cause of miscarriages and chromosomal abnormalities such as Down’s syndrome. Recombination is initiated by the formation of programmed double strand breaks (DSBs), which occur preferentially at places called DSB hotspots. Among all DSBs generated, only a small fraction is repaired by crossover, the other being repaired by other homologous recombination pathways. Crossover maps have been generated in a number of organisms, defining crossover hotspots. With the availability of genome-wide maps of DSBs as well as the ability to measure genetically the repair outcome at several hotspots, it is becoming more and more clear that not all DSB hotspots behave the same for crossover formation, suggesting that chromosomal features distinguish different types of hotspots.

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Elsa Brachet, Vérane Sommermeyer, Valérie Borde (2012 Feb 23)

Interplay between modifications of chromatin and meiotic recombination hotspots.

Biology of the cell / under the auspices of the European Cell Biology Organization : 51-69 : DOI : 10.1111/boc.201100113 En savoir plus
Résumé

Meiotic recombination lies at the heart of sexual reproduction. It is essential for producing viable gametes with a normal haploid genomic content and its dysfunctions can be at the source of aneuploidies, such as the Down syndrome, or many genetic disorders. Meiotic recombination also generates genetic diversity that is transmitted to progeny by shuffling maternal and paternal alleles along chromosomes. Recombination takes place at non-random chromosomal sites called ‘hotspots’. Recent evidence has shown that their location is influenced by properties of chromatin. In addition, many studies in somatic cells have highlighted the need for changes in chromatin dynamics to allow the process of recombination. In this review, we discuss how changes in the chromatin landscape may influence the recombination map, and reciprocally, how recombination events may lead to epigenetic modifications at sites of recombination, which could be transmitted to progeny.

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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

Michael B Clark, Paulo P Amaral, Felix J Schlesinger, Marcel E Dinger, Ryan J Taft, John L Rinn, Chris P Ponting, Peter F Stadler, Kevin V Morris, Antonin Morillon, Joel S Rozowsky, Mark B Gerstein, Claes Wahlestedt, Yoshihide Hayashizaki, Piero Carninci, Thomas R Gingeras, John S Mattick (2011 Jul 19)

The reality of pervasive transcription.

PLoS biology : e1000625; discussion e1001102 : DOI : 10.1371/journal.pbio.1000625 En savoir plus
Résumé

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Marion Dubarry, Isabelle Loïodice, Chunlong L Chen, Claude Thermes, Angela Taddei (2011 Jul 5)

Tight protein-DNA interactions favor gene silencing.

Genes & development : 1365-70 : DOI : 10.1101/gad.611011 En savoir plus
Résumé

The heterochromatin-like structure formed by the yeast silent information regulator complex (SIR) represses transcription at the silent mating type loci and telomeres. Here, we report that tight protein-DNA complexes induce ectopic recruitment of the SIR complex, promoting gene silencing and changes in subnuclear localization when cis-acting elements are nearby. Importantly, lack of the replication fork-associated helicase Rrm3 enhances this induced gene repression. Additionally, Sir3 and Sir4 are enriched genome-wide at natural replication pause sites, including tRNA genes. Consistently, inserting a tRNA gene promotes SIR-mediated silencing of a nearby gene. These results reveal that replication stress arising from tight DNA-protein interactions favors heterochromatin formation.

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Bruno Cosnier, Marta Kwapisz, Isabelle Hatin, Olivier Namy, Sylvie Hermann-Le Denmat, Antonin Morillon, Jean-Pierre Rousset, Céline Fabret (2011 May 12)

A viable hypomorphic allele of the essential IMP3 gene reveals novel protein functions in Saccharomyces cerevisiae.

PloS one : e19500 : DOI : 10.1371/journal.pone.0019500 En savoir plus
Résumé

In Saccharomyces cerevisiae, the essential IMP3 gene encodes a component of the SSU processome, a large ribonucleoprotein complex required for processing of small ribosomal subunit RNA precursors. Mutation of the IMP3 termination codon to a sense codon resulted in a viable mutant allele producing a C-terminal elongated form of the Imp3 protein. A strain expressing the mutant allele displayed ribosome biogenesis defects equivalent to IMP3 depletion. This hypomorphic allele represented a unique opportunity to investigate and better understand the Imp3p functions. We demonstrated that the +1 frameshifting was increased in the mutant strain. Further characterizations revealed involvement of the Imp3 protein in DNA repair and telomere length control, pointing to a functional relationship between both pathways and ribosome biogenesis.

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