UMR3244 – Dynamique de l’information génétique

Publications de l’équipe

Année de publication : 2016

Robert Jackson, Bruce A Rosa, Sonia Lameiras, Sean Cuninghame, Josee Bernard, Wely B Floriano, Paul F Lambert, Alain Nicolas, Ingeborg Zehbe (2016 Nov 4)

Functional variants of human papillomavirus type 16 demonstrate host genome integration and transcriptional alterations corresponding to their unique cancer epidemiology.

BMC genomics : 851 En savoir plus
Résumé

Human papillomaviruses (HPVs) are a worldwide burden as they are a widespread group of tumour viruses in humans. Having a tropism for mucosal tissues, high-risk HPVs are detected in nearly all cervical cancers. HPV16 is the most common high-risk type but not all women infected with high-risk HPV develop a malignant tumour. Likely relevant, HPV genomes are polymorphic and some HPV16 single nucleotide polymorphisms (SNPs) are under evolutionary constraint instigating variable oncogenicity and immunogenicity in the infected host.

Replier
Pierre Thouvenot, Lou Fourrière, Elodie Dardillac, Barbara Ben Yamin, Aurianne Lescure, Vincent Lejour, Xavier Heiligenstein, Jean-Baptiste Boulé, Maryse Romao, Graça Raposo-Benedetti, Bernard S Lopez, Alain Nicolas, Gaël A Millot (2016 Nov 2)

Yeast cells reveal the misfolding and the cellular mislocalisation of the human BRCA1 protein.

Journal of cell science : DOI : jcs.192880 En savoir plus
Résumé

Understanding the effect of an ever-growing number of human variants detected by genome sequencing is a medical challenge. The yeast Saccharomyces cerevisiae model has held attention for its capacity to monitor the functional impact of missense mutations found in human genes, including the BRCA1 breast/ovarian cancer susceptibility gene. When expressed in yeast, the wild-type full-length BRCA1 protein forms a single nuclear aggregate and induces a growth inhibition. Both events are modified by pathogenic mutations of BRCA1. However, the biological interpretation of these events remains to be determined. Here, we show that the BRCA1 nuclear aggregation and the growth inhibition are sensitive to misfolding effects induced by missense mutations. Moreover, misfolding mutations impair the nuclear targeting of BRCA1 in yeast cells and in a human cell line. In conclusion, we establish a connection between misfolding and nuclear transport impairment and we illustrate that yeast is a suitable model to decipher the effect of misfolding mutations.

Replier
Loic Verlingue, Aurélien Dugourd, Gautier Stoll, Emmanuel Barillot, Laurence Calzone, Arturo Londoño-Vallejo (2016 Sep 11)

A comprehensive approach to the molecular determinants of lifespan using a Boolean model of geroconversion.

Aging cell : DOI : 10.1111/acel.12504 En savoir plus
Résumé

Altered molecular responses to insulin and growth factors (GF) are responsible for late-life shortening diseases such as type-2 diabetes mellitus (T2DM) and cancers. We have built a network of the signaling pathways that control S-phase entry and a specific type of senescence called geroconversion. We have translated this network into a Boolean model to study possible cell phenotype outcomes under diverse molecular signaling conditions. In the context of insulin resistance, the model was able to reproduce the variations of the senescence level observed in tissues related to T2DM’s main morbidity and mortality. Furthermore, by calibrating the pharmacodynamics of mTOR inhibitors, we have been able to reproduce the dose-dependent effect of rapamycin on liver degeneration and lifespan expansion in wild-type and HER2-neu mice. Using the model, we have finally performed an in silico prospective screen of the risk-benefit ratio of rapamycin dosage for healthy lifespan expansion strategies. We present here a comprehensive prognostic and predictive systems biology tool for human aging.

Replier
Franck Toledo (2016 Aug 20)

p53: A two-faced regulator of telomere metabolism? (comment on DOI 10.1002/bies.201600078).

BioEssays : news and reviews in molecular, cellular and developmental biology : DOI : 10.1002/bies.201600149 En savoir plus
Résumé

Replier
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
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
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
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