UMR3244 – Dynamique de l’information génétique

Publications de l’équipe

Année de publication : 2016

Alvaro de Andres-Pablo, Antonin Morillon, Maxime Wery (2016 May 28)

LncRNAs, lost in translation or licence to regulate?

Current genetics En savoir plus
Résumé

Over the last decade, advances in transcriptomics have revealed that the pervasive transcription of eukaryotic genomes produces plethora of long noncoding RNAs (lncRNAs), which are now recognized as major regulators of multiple cellular processes. Although they have been thought to lack any protein-coding potential, recent ribosome-profiling data indicate that lncRNAs can interact with the translation machinery, leading to the production of functional peptides in some cases. In this perspective, we have explored the idea that translation can be part of the fate of cytoplasmic lncRNAs, raising the possibility for them to work as bifunctional RNAs, endowed with dual coding and regulatory functions.

Replier
Holmes A., Lameiras S., Jeannot E., Marie Y., Castera L., Sastre-Garau X., Nicolas A. (2016 May 16)

Mechanistic signatures of HPV insertions in cervical carcinomas

Nature Genomic Medicine : DOI : 10.1038/npjgenmed.2016.4 En savoir plus
Résumé

Replier
Sara Jaber, Eléonore Toufektchan, Vincent Lejour, Boris Bardot, Franck Toledo (2016 Apr 2)

p53 downregulates the Fanconi anaemia DNA repair pathway.

Nature communications : 11091 : DOI : 10.1038/ncomms11091 En savoir plus
Résumé

Germline mutations affecting telomere maintenance or DNA repair may, respectively, cause dyskeratosis congenita or Fanconi anaemia, two clinically related bone marrow failure syndromes. Mice expressing p53(Δ31), a mutant p53 lacking the C terminus, model dyskeratosis congenita. Accordingly, the increased p53 activity in p53(Δ31/Δ31) fibroblasts correlated with a decreased expression of 4 genes implicated in telomere syndromes. Here we show that these cells exhibit decreased mRNA levels for additional genes contributing to telomere metabolism, but also, surprisingly, for 12 genes mutated in Fanconi anaemia. Furthermore, p53(Δ31/Δ31) fibroblasts exhibit a reduced capacity to repair DNA interstrand crosslinks, a typical feature of Fanconi anaemia cells. Importantly, the p53-dependent downregulation of Fanc genes is largely conserved in human cells. Defective DNA repair is known to activate p53, but our results indicate that, conversely, an increased p53 activity may attenuate the Fanconi anaemia DNA repair pathway, defining a positive regulatory feedback loop.

Replier
Vijayalakshmi V Subramanian, Amy J MacQueen, Gerben Vader, Miki Shinohara, Aurore Sanchez, Valérie Borde, Akira Shinohara, Andreas Hochwagen (2016 Feb 13)

Chromosome Synapsis Alleviates Mek1-Dependent Suppression of Meiotic DNA Repair.

PLoS biology : e1002369 : DOI : 10.1371/journal.pbio.1002369 En savoir plus
Résumé

Faithful meiotic chromosome segregation and fertility require meiotic recombination between homologous chromosomes rather than the equally available sister chromatid, a bias that in Saccharomyces cerevisiae depends on the meiotic kinase, Mek1. Mek1 is thought to mediate repair template bias by specifically suppressing sister-directed repair. Instead, we found that when Mek1 persists on closely paired (synapsed) homologues, DNA repair is severely delayed, suggesting that Mek1 suppresses any proximal repair template. Accordingly, Mek1 is excluded from synapsed homologues in wild-type cells. Exclusion requires the AAA+-ATPase Pch2 and is directly coupled to synaptonemal complex assembly. Stage-specific depletion experiments further demonstrate that DNA repair in the context of synapsed homologues requires Rad54, a repair factor inhibited by Mek1. These data indicate that the sister template is distinguished from the homologue primarily by its closer proximity to inhibitory Mek1 activity. We propose that once pairing or synapsis juxtaposes homologues, exclusion of Mek1 is necessary to avoid suppression of all templates and accelerate repair progression.

Replier
Laurent Jullien, Caroline Kannengiesser, Laetitia Kermasson, Valérie Cormier-Daire, Thierry Leblanc, Jean Soulier, Arturo Londono-Vallejo, Jean-Pierre de Villartay, Isabelle Callebaut, Patrick Revy (2016 Feb 6)

Mutations of the RTEL1 Helicase in a Hoyeraal-Hreidarsson Syndrome Patient Highlight the Importance of the ARCH Domain.

Human mutation : 469-72 : DOI : 10.1002/humu.22966 En savoir plus
Résumé

The DNA helicase RTEL1 participates in telomere maintenance and genome stability. Biallelic mutations in the RTEL1 gene account for the severe telomere biology disorder characteristic of the Hoyeraal-Hreidarsson syndrome (HH). Here, we report a HH patient (P4) carrying two novel compound heterozygous mutations in RTEL1: a premature stop codon (c.949A>T, p.Lys317*) and an intronic deletion leading to an exon skipping and an in-frame deletion of 25 amino-acids (p.Ile398_Lys422). P4’s cells exhibit short and dysfunctional telomeres similarly to other RTEL1-deficient patients. 3D structure predictions indicated that the p.Ile398_Lys422 deletion affects a part of the helicase ARCH domain, which lines the pore formed with the core HD and the iron-sulfur cluster domains and is highly specific of sequences from the eukaryotic XPD family members.

Replier
Maxime Wery, Marc Descrimes, Nicolas Vogt, Anne-Sophie Dallongeville, Daniel Gautheret, Antonin Morillon (2016 Jan 26)

Nonsense-Mediated Decay Restricts LncRNA Levels in Yeast Unless Blocked by Double-Stranded RNA Structure.

Molecular cell : 379-92 : DOI : 10.1016/j.molcel.2015.12.020 En savoir plus
Résumé

Antisense long non-coding (aslnc)RNAs represent a substantial part of eukaryotic transcriptomes that are, in yeast, controlled by the Xrn1 exonuclease. Nonsense-Mediated Decay (NMD) destabilizes the Xrn1-sensitive aslncRNAs (XUT), but what determines their sensitivity remains unclear. We report that 3′ single-stranded (3′-ss) extension mediates XUTs degradation by NMD, assisted by the Mtr4 and Dbp2 helicases. Single-gene investigation, genome-wide RNA analyses, and double-stranded (ds)RNA mapping revealed that 3′-ss extensions discriminate the NMD-targeted XUTs from stable lncRNAs. Ribosome profiling showed that XUT are translated, locking them for NMD activity. Interestingly, mutants of the Mtr4 and Dbp2 helicases accumulated XUTs, suggesting that dsRNA unwinding is a critical step for degradation. Indeed, expression of anticomplementary transcripts protects cryptic intergenic lncRNAs from NMD. Our results indicate that aslncRNAs form dsRNA that are only translated and targeted to NMD if dissociated by Mtr4 and Dbp2. We propose that NMD buffers genome expression by discarding pervasive regulatory transcripts.

Replier
Hervé Técher, Stéphane Koundrioukoff, Sandra Carignon, Therese Wilhelm, Gaël A Millot, Bernard S Lopez, Olivier Brison, Michelle Debatisse (2016 Jan 26)

Signaling from Mus81-Eme2-Dependent DNA Damage Elicited by Chk1 Deficiency Modulates Replication Fork Speed and Origin Usage.

Cell reports : 1114-27 : DOI : 10.1016/j.celrep.2015.12.093 En savoir plus
Résumé

Mammalian cells deficient in ATR or Chk1 display moderate replication fork slowing and increased initiation density, but the underlying mechanisms have remained unclear. We show that exogenous deoxyribonucleosides suppress both replication phenotypes in Chk1-deficient, but not ATR-deficient, cells. Thus, in the absence of exogenous stress, depletion of either protein impacts the replication dynamics through different mechanisms. In addition, Chk1 deficiency, but not ATR deficiency, triggers nuclease-dependent DNA damage. Avoiding damage formation through invalidation of Mus81-Eme2 and Mre11, or preventing damage signaling by turning off the ATM pathway, suppresses the replication phenotypes of Chk1-deficient cells. Damage and resulting DDR activation are therefore the cause, not the consequence, of replication dynamics modulation in these cells. Together, we identify moderate reduction of precursors available for replication as an additional outcome of DDR activation. We propose that resulting fork slowing, and subsequent firing of backup origins, helps replication to proceed along damaged templates.

Replier
Delphine Benarroch-Popivker, Sabrina Pisano, Aaron Mendez-Bermudez, Liudmyla Lototska, Parminder Kaur, Serge Bauwens, Nadir Djerbi, Chrysa M Latrick, Vincent Fraisier, Bei Pei, Alexandre Gay, Emilie Jaune, Kevin Foucher, Julien Cherfils-Vicini, Eric Aeby, Simona Miron, Arturo Londoño-Vallejo, Jing Ye, Marie-Hélène Le Du, Hong Wang, Eric Gilson, Marie-Josèphe Giraud-Panis (2016 Jan 18)

TRF2-Mediated Control of Telomere DNA Topology as a Mechanism for Chromosome-End Protection.

Molecular cell : 274-86 : DOI : 10.1016/j.molcel.2015.12.009 En savoir plus
Résumé

The shelterin proteins protect telomeres against activation of the DNA damage checkpoints and recombinational repair. We show here that a dimer of the shelterin subunit TRF2 wraps ∼ 90 bp of DNA through several lysine and arginine residues localized around its homodimerization domain. The expression of a wrapping-deficient TRF2 mutant, named Top-less, alters telomeric DNA topology, decreases the number of terminal loops (t-loops), and triggers the ATM checkpoint, while still protecting telomeres against non-homologous end joining (NHEJ). In Top-less cells, the protection against NHEJ is alleviated if the expression of the TRF2-interacting protein RAP1 is reduced. We conclude that a distinctive topological state of telomeric DNA, controlled by the TRF2-dependent DNA wrapping and linked to t-loop formation, inhibits both ATM activation and NHEJ. The presence of RAP1 at telomeres appears as a backup mechanism to prevent NHEJ when topology-mediated telomere protection is impaired.

Replier

Année de publication : 2015

Jia Li, Marie-Anne Poursat, Damien Drubay, Arnaud Motz, Zohra Saci, Antonin Morillon, Stefan Michiels, Daniel Gautheret (2015 Nov 21)

A Dual Model for Prioritizing Cancer Mutations in the Non-coding Genome Based on Germline and Somatic Events.

PLoS computational biology : e1004583 : DOI : 10.1371/journal.pcbi.1004583 En savoir plus
Résumé

We address here the issue of prioritizing non-coding mutations in the tumoral genome. To this aim, we created two independent computational models. The first (germline) model estimates purifying selection based on population SNP data. The second (somatic) model estimates tumor mutation density based on whole genome tumor sequencing. We show that each model reflects a different set of constraints acting either on the normal or tumor genome, and we identify the specific genome features that most contribute to these constraints. Importantly, we show that the somatic mutation model carries independent functional information that can be used to narrow down the non-coding regions that may be relevant to cancer progression. On this basis, we identify positions in non-coding RNAs and the non-coding parts of mRNAs that are both under purifying selection in the germline and protected from mutation in tumors, thus introducing a new strategy for future detection of cancer driver elements in the expressed non-coding genome.

Replier
Boris Bardot, Franck Toledo (2015 Nov 4)

Mdm4: don’t judge an isoform by its mRNA levels!

Aging : 744-5 En savoir plus
Résumé

Replier
Mohamed Izikki, Eric Hoang, Irena Draskovic, Olaf Mercier, Florence Lecerf, Lilia Lamrani, Win-Yan Liu, Christophe Guignabert, Elie Fadel, Peter Dorfmuller, Marc Humbert, Arturo Londoño-Vallejo, Saadia Eddahibi (2015 Oct 24)

Telomere Maintenance Is a Critical Determinant in the Physiopathology of Pulmonary Hypertension.

Journal of the American College of Cardiology : 1942-3 : DOI : 10.1016/j.jacc.2015.08.869 En savoir plus
Résumé

Replier
Marc Descrimes, Yousra Ben Zouari, Maxime Wery, Rachel Legendre, Daniel Gautheret, Antonin Morillon (2015 Sep 9)

VING: a software for visualization of deep sequencing signals.

BMC research notes : 419 : DOI : 10.1186/s13104-015-1404-5 En savoir plus
Résumé

Next generation sequencing (NGS) data treatment often requires mapping sequenced reads onto a reference genome for further analysis. Mapped data are commonly visualized using genome browsers. However, such software are not suited for a publication-ready and versatile representation of NGS data coverage, especially when multiple experiments are simultaneously treated.

Replier
Flore Sinturel, Albertas Navickas, Maxime Wery, Marc Descrimes, Antonin Morillon, Claire Torchet, Lionel Benard (2015 Sep 8)

Cytoplasmic Control of Sense-Antisense mRNA Pairs.

Cell reports : 1853-64 : DOI : 10.1016/j.celrep.2015.08.016 En savoir plus
Résumé

Transcriptome analyses have revealed that convergent gene transcription can produce many 3′-overlapping mRNAs in diverse organisms. Few studies have examined the fate of 3′-complementary mRNAs in double-stranded RNA-dependent nuclear phenomena, and nothing is known about the cytoplasmic destiny of 3′-overlapping messengers or their impact on gene expression. Here, we demonstrate that the complementary tails of 3′-overlapping mRNAs can interact in the cytoplasm and promote post-transcriptional regulatory events including no-go decay (NGD) in Saccharomyces cerevisiae. Genome-wide experiments confirm that these messenger-interacting mRNAs (mimRNAs) form RNA duplexes in wild-type cells and thus have potential roles in modulating the mRNA levels of their convergent gene pattern under different growth conditions. We show that the post-transcriptional fate of hundreds of mimRNAs is controlled by Xrn1, revealing the extent to which this conserved 5′-3′ cytoplasmic exoribonuclease plays an unexpected but key role in the post-transcriptional control of convergent gene expression.

Replier
Nicola Manfrini, Michela Clerici, Maxime Wery, Chiara Vittoria Colombo, Marc Descrimes, Antonin Morillon, Fabrizio d'Adda di Fagagna, Maria Pia Longhese (2015 Aug 1)

Resection is responsible for loss of transcription around a double-strand break in Saccharomyces cerevisiae.

eLife : DOI : 10.7554/eLife.08942 En savoir plus
Résumé

Emerging evidence indicate that the mammalian checkpoint kinase ATM induces transcriptional silencing in cis to DNA double-strand breaks (DSBs) through a poorly understood mechanism. Here we show that in Saccharomyces cerevisiae a single DSB causes transcriptional inhibition of proximal genes independently of Tel1/ATM and Mec1/ATR. Since the DSB ends undergo nucleolytic degradation (resection) of their 5′-ending strands, we investigated the contribution of resection in this DSB-induced transcriptional inhibition. We discovered that resection-defective mutants fail to stop transcription around a DSB, and the extent of this failure correlates with the severity of the resection defect. Furthermore, Rad9 and generation of γH2A reduce this DSB-induced transcriptional inhibition by counteracting DSB resection. Therefore, the conversion of the DSB ends from double-stranded to single-stranded DNA, which is necessary to initiate DSB repair by homologous recombination, is responsible for loss of transcription around a DSB in S. cerevisiae.

Replier
Luis Jaime Castro-Vega, Karina Jouravleva, Paola Ortiz-Montero, Win-Yan Liu, Jorge Luis Galeano, Martha Romero, Tatiana Popova, Silvia Bacchetti, Jean Paul Vernot, Arturo Londoño-Vallejo (2015 Jul 15)

The senescent microenvironment promotes the emergence of heterogeneous cancer stem-like cells.

Carcinogenesis : 1180-92 : DOI : 10.1093/carcin/bgv101 En savoir plus
Résumé

There is a well-established association between aging and the onset of metastasis. Although the mechanisms through which age impinges upon the malignant phenotype remain uncharacterized, the role of a senescent microenvironment has been emphasized. We reported previously that human epithelial cells that undergo telomere-driven chromosome instability (T-CIN) display global microRNA (miR) deregulation and develop migration and invasion capacities. Here, we show that post-crisis cells are not able to form tumors unless a senescent microenvironment is provided. The characterization of cell lines established from such tumors revealed that these cells have acquired cell autonomous tumorigenicity, giving rise to heterogeneous tumors. Further experiments demonstrate that explanted cells, while displaying differences in cell differentiation markers, are all endowed of enhanced stem cell properties including self-renewal and multilineage differentiation capacity. Treatments of T-CIN+ cells with senescence-conditioned media induce sphere formation exclusively in cells with senescence-associated tumorigenicity, a capacity that depends on miR-145 repression. These results indicate that the senescent microenvironment, while promoting further transdifferentiations in cells with genome instability, is able to propel the progression of premalignant cells towards a malignant, cell stem-like state.

Replier