UMR3348 – Intégrité du génome, ARN et cancer

Publications de l’unité

Année de publication : 2017

Zeina Bash-Imam, Gabriel Thérizols, Anne Vincent, Florian Lafôrets, Micaela Polay Espinoza, Nathalie Pion, Françoise Macari, Julie Pannequin, Alexandre David, Jean-Christophe Saurin, Hichem C Mertani, Julien Textoris, Didier Auboeuf, Frédéric Catez, Nicole Dalla Venezia, Martin Dutertre, Virginie Marcel, Jean-Jacques Diaz (2017 Jul 11)

Translational reprogramming of colorectal cancer cells induced by 5-fluorouracil through a miRNA-dependent mechanism.

Oncotarget : 46219-46233 : DOI : 10.18632/oncotarget.17597 En savoir plus
Résumé

5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug in colorectal cancer. Previous studies showed that 5-FU modulates RNA metabolism and mRNA expression. In addition, it has been reported that 5-FU incorporates into the RNAs constituting the translational machinery and that 5-FU affects the amount of some mRNAs associated with ribosomes. However, the impact of 5-FU on translational regulation remains unclear. Using translatome profiling, we report that a clinically relevant dose of 5-FU induces a translational reprogramming in colorectal cancer cell lines. Comparison of mRNA distribution between polysomal and non-polysomal fractions in response to 5-FU treatment using microarray quantification identified 313 genes whose translation was selectively regulated. These regulations were mostly stimulatory (91%). Among these genes, we showed that 5-FU increases the mRNA translation of HIVEP2, which encodes a transcription factor whose translation in normal condition is known to be inhibited by mir-155. In response to 5-FU, the expression of mir-155 decreases thus stimulating the translation of HIVEP2 mRNA. Interestingly, the 5-FU-induced increase in specific mRNA translation was associated with reduction of global protein synthesis. Altogether, these findings indicate that 5-FU promotes a translational reprogramming leading to the increased translation of a subset of mRNAs that involves at least for some of them, miRNA-dependent mechanisms. This study supports a still poorly evaluated role of translational control in drug response.

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Simon Gemble, Géraldine Buhagiar-Labarchède, Rosine Onclercq-Delic, Christian Jaulin, Mounira Amor-Guéret (2017 Jun 3)

Cytidine deaminase deficiency impairs sister chromatid disjunction by decreasing PARP-1 activity.

Cell cycle (Georgetown, Tex.) : 1-8 : DOI : 10.1080/15384101.2017.1317413 En savoir plus
Résumé

Bloom Syndrome (BS) is a rare genetic disease characterized by high levels of chromosomal instability and an increase in cancer risk. Cytidine deaminase (CDA) expression is downregulated in BS cells, leading to an excess of cellular dC and dCTP that reduces basal PARP-1 activity, compromising optimal Chk1 activation and reducing the efficiency of downstream checkpoints. This process leads to the accumulation of unreplicated DNA during mitosis and, ultimately, ultrafine anaphase bridge (UFB) formation. BS cells also display incomplete sister chromatid disjunction when depleted of cohesin. Using a combination of fluorescence in situ hybridization and chromosome spreads, we investigated the possible role of CDA deficiency in the incomplete sister chromatid disjunction in cohesin-depleted BS cells. The decrease in basal PARP-1 activity in CDA-deficient cells compromised sister chromatid disjunction in cohesin-depleted cells, regardless of BLM expression status. The observed incomplete sister chromatid disjunction may be due to the accumulation of unreplicated DNA during mitosis in CDA-deficient cells, as reflected in the changes in centromeric DNA structure associated with the decrease in basal PARP-1 activity. Our findings reveal a new function of PARP-1 in sister chromatid disjunction during mitosis.

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Kathiresan Natarajan, Sudarshan Gadadhar, Judith Souphron, Maria M Magiera, Carsten Janke (2017 Jun 1)

Molecular interactions between tubulin tails and glutamylases reveal determinants of glutamylation patterns.

EMBO reports : 1013-1026 : DOI : 10.15252/embr.201643751 En savoir plus
Résumé

Posttranslational modifications of tubulin currently emerge as key regulators of microtubule functions. Polyglutamylation generates a variety of modification patterns that are essential for controlling microtubule functions in different cell types and organelles, and deregulation of these patterns has been linked to ciliopathies, cancer and neurodegeneration. How the different glutamylating enzymes determine precise modification patterns has so far remained elusive. Using computational modelling, molecular dynamics simulations and mutational analyses we now show how the carboxy-terminal tails of tubulin bind into the active sites of glutamylases. Our models suggest that the glutamylation sites on α- and β-tubulins are determined by the positioning of the tails within the catalytic pocket. Moreover, we found that the binding modes of α- and β-tubulin tails are highly similar, implying that most enzymes could potentially modify both, α- and β-tubulin. This supports a model in which the binding of the enzymes to the entire microtubule lattice, but not the specificity of the C-terminal tubulin tails to their active sites, determines the catalytic specificities of glutamylases.

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Hermela Shimelis, Romy L S Mesman, Catharina Von Nicolai, Asa Ehlen, Lucia Guidugli, Charlotte Martin, Fabienne Mgr Calleja, Huong Meeks, Emily Hallberg, Jamie Hinton, Jenna Lilyquist, Chunling Hu, Cora M Aalfs, Kristiina Aittomaki, Irene L Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias W Beckmann, Javier J Benitez, Natalia Bogdanova, Stig E Bojesen, Manjeet K Bolla, Anne-Lise Borresen-Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Annegien Broeks, Barbara Brouwers, Thomas Bruning, Barbara Burwinkel, Jenny Chang-Claude, Georgia Chenevix-Trench, Ching-Yu Cheng, Ji-Yeob Choi, J Margriet Collée, Angela Cox, Simon S Cross, Kamila Czene, Hatef Darabi, Joe Dennis, Thilo Dork, Isabel Dos Santos Silva, Alison M Dunning, Peter A Fasching, Jonine D Figueroa, Henrik Flyger, Montserrat Garcia-Closas, Graham G Giles, Gord Glendon, Pascal Guenel, Christopher A Haiman, Per Hall, Ute Hamann, Mikael Hartman, Frans B L Hogervorst, Antoinette Hollestelle, John L Hopper, Hidemi Ito, Anna Jakubowska, Daehee Kang, Veli-Matti Kosma, Vessela Kristensen, Kah-Nyin Lai, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Annika Lindblom, Artitaya Lophatananon, Jan Lubinski, Eva Machackova, Arto Mannermaa, Sara Margolin, Frederik Marme, Keitaro Matsuo, Hui Miao, Kyriaki Michailidou, Roger L Milne, Kenneth Muir, Susan L Neuhausen, Heli Nevanlinna, Janet E Olson, Curtis Olswold, Jan C Oosterwijk, Ana Osorio, Paolo Peterlongo, Julian Peto, Paul D P Pharoah, Katri Pylkäs, Paolo Radice, Muhammad U Rashid, Valerie Rhenius, Anja Rudolph, Suleeporn Sangrajrang, Elinor J Sawyer, Marjanka K Schmidt, Minouk J Schoemaker, Caroline M Seynaeve, Mitul Shah, Chen-Yang Shen, Martha J Shrubsole, Xiao-Ou Shu, Susan L Slager, Melissa C Southey, Daniel O Stram, Anthony J Swerdlow, Soo Hwang Teo, Ian Tomlinson, Diana Torres, Therese Truong, Christi J van Asperen, Lizet E van der Kolk, Qin Wang, Robert Winqvist, Anna H Wu, Jyh-Cherng Yu, Wei Zheng, Ying Zheng, Jennifer Leary, Logan C Walker, Lenka Foretova, Florentia Fostira, Kathleen Claes, Liliana Varesco, Setareh Moghadasi, Douglas F Easton, Amanda B Spurdle, Peter Devilee, Harry Vrieling, Alvaro N Monteiro, David E Goldgar, Aura Carreira, Maaike P G Vreeswijk, Fergus J Couch (2017 Jun 1)

BRCA2 hypomorphic missense variants confer moderate risks of breast cancer.

Cancer research : DOI : 10.1158/0008-5472.CAN-16-2568 En savoir plus
Résumé

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR=2.52, p=0.04) and BRCA1 c.5096G>A, p.Arg1699Gln (OR=4.29, p=0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR=2.68, p=0.004) and c.8187G>T, p.Lys2729Asn (OR=1.4, p=0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared to wildtype. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants.

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Anissia Ait Saada, Ana Teixeira-Silva, Ismail Iraqui, Audrey Costes, Julien Hardy, Giulia Paoletti, Karine Fréon, Sarah A E Lambert (2017 May 4)

Unprotected Replication Forks Are Converted into Mitotic Sister Chromatid Bridges.

Molecular cell : 398-410.e4 : DOI : 10.1016/j.molcel.2017.04.002 En savoir plus
Résumé

Replication stress and mitotic abnormalities are key features of cancer cells. Temporarily paused forks are stabilized by the intra-S phase checkpoint and protected by the association of Rad51, which prevents Mre11-dependent resection. However, if a fork becomes dysfunctional and cannot resume, this terminally arrested fork is rescued by a converging fork to avoid unreplicated parental DNA during mitosis. Alternatively, dysfunctional forks are restarted by homologous recombination. Using fission yeast, we report that Rad52 and the DNA binding activity of Rad51, but not its strand-exchange activity, act to protect terminally arrested forks from unrestrained Exo1-nucleolytic activity. In the absence of recombination proteins, large ssDNA gaps, up to 3 kb long, occur behind terminally arrested forks, preventing efficient fork merging and leading to mitotic sister chromatid bridging. Thus, Rad52 and Rad51 prevent temporarily and terminally arrested forks from degrading and, despite the availability of converging forks, converting to anaphase bridges causing aneuploidy and cell death.

Free acces : authors.elsevier.com/a/1U~li3vVUP2C0m

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Hamza Mameri, Ivan Bieche, Dider Meseure, Elisabetta Marangoni, Géraldine Buhagiar-Labarchède, Andre Nicolas, Sophie Vacher, Rosine Onclercq-Delic, Vinodh Rajapakse, Sudhir Varma, William C Reinhold, Yves Pommier, Mounira Amor-Guéret (2017 Apr 15)

Cytidine deaminase deficiency reveals new therapeutic opportunities against cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research : DOI : 10.1158/1078-0432.CCR-16-0626 En savoir plus
Résumé

One of the main challenges in cancer therapy is the identification of molecular mechanisms mediating resistance or sensitivity to treatment. Cytidine deaminase (CDA) was reported to be downregulated in cells derived from patients with Bloom syndrome, a genetic disease associated with a strong predisposition to a wide range of cancers. The purpose of this study was to determine whether CDA deficiency could be associated with tumors from the general population and could constitute a predictive marker of susceptibility to anti-tumor drugs.

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Sudarshan Gadadhar, Satish Bodakuntla, Kathiresan Natarajan, Carsten Janke (2017 Apr 15)

The tubulin code at a glance.

Journal of cell science : 1347-1353 : DOI : 10.1242/jcs.199471 En savoir plus
Résumé

Microtubules are key cytoskeletal elements of all eukaryotic cells and are assembled of evolutionarily conserved α-tubulin-β-tubulin heterodimers. Despite their uniform structure, microtubules fulfill a large diversity of functions. A regulatory mechanism to control the specialization of the microtubule cytoskeleton is the ‘tubulin code’, which is generated by (i) expression of different α- and β-tubulin isotypes, and by (ii) post-translational modifications of tubulin. In this Cell Science at a Glance article and the accompanying poster, we provide a comprehensive overview of the molecular components of the tubulin code, and discuss the mechanisms by which these components contribute to the generation of functionally specialized microtubules.

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Christine Tran Quang, Benedetta Zaniboni, Jacques Ghysdael (2017 Mar 31)

A TCR-switchable cell death pathway in T-ALL.

Oncoscience : 17-18 : DOI : 10.18632/oncoscience.342 En savoir plus
Résumé

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Akendengue L., Trepout S., Grana M., Voegele A., Janke C., Raynal B., Chenal A., Marco S., Wehenkel A.M. (2017 Mar 30)

Bacterial kinesin light chain (Bklc) links the Btub cytoskeleton to membranes

Scientific Reports : 7 : 45668 : DOI : 10.1038/srep45668 En savoir plus
Résumé

Bacterial kinesin light chain is a TPR domain-containing protein encoded by the bklc gene, which co-localizes with the bacterial tubulin (btub) genes in a conserved operon in Prosthecobacter. Btub heterodimers show high structural homology with eukaryotic tubulin and assemble into head-to-tail protofilaments. Intriguingly, Bklc is homologous to the light chain of the microtubule motor kinesin and could thus represent an additional eukaryotic-like cytoskeletal element in bacteria. Using biochemical characterization as well as cryo-electron tomography we show here that Bklc interacts specifically with Btub protofilaments, as well as lipid vesicles and could thus play a role in anchoring the Btub filaments to the membrane protrusions in Prosthecobacter where they specifically localize in vivo. This work sheds new light into possible ways in which the microtubule cytoskeleton may have evolved linking precursors of microtubules to the membrane via the kinesin moiety that in today’s eukaryotic cytoskeleton links vesicle-packaged cargo to microtubules.

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Montserrat Bosch Grau, Christel Masson, Sudarshan Gadadhar, Cecilia Rocha, Olivia Tort, Patricia Marques Sousa, Sophie Vacher, Ivan Bieche, Carsten Janke (2017 Mar 1)

Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration.

Journal of cell science : DOI : 10.1242/jcs.199091 En savoir plus
Résumé

Tubulin is subject to a wide variety of posttranslational modifications, which as part of the tubulin code are involved in the regulation of microtubule functions. Glycylation has so far predominantly been found in motile cilia and flagella, and absence of this modification leads to ciliary disassembly. Here we demonstrate that the connecting cilia of photoreceptors, which are non-motile sensory cilia, are also dependent on glycylation. In contrast to many other tissues, only one glycylase, TTLL3, is expressed in retina. Ttll3(-/-) mice lack glycylation in photoreceptors, which results in shortening of connecting cilia and slow retinal degeneration. Moreover, absence of glycylation results in increased levels of tubulin glutamylation in photoreceptors, and inversely, hyperglutamylation in the pcd mouse abolishes glycylation. This suggests that both posttranslational modifications compete for modification sites, and that unbalancing the glutamylation/glycylation equilibrium on axonemes of connecting cilia, notwithstanding by which enzymatic mechanism, invariably leads to retinal degeneration.

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Helene Malka-Mahieu, Michelle Newman, Laurent Desaubry, Caroline Robert, Stephan Vagner (2017 Jan 1)

Molecular Pathways: The eIF4F Translation Initiation Complex- New Opportunities for Cancer Treatment.

Clinical cancer research : an official journal of the American Association for Cancer Research : DOI : 10.1158/1078-0432.CCR-14-2362 En savoir plus
Résumé

The eIF4F complex regulates the cap-dependent mRNA translation process. It is becoming increasingly evident that aberrant activity of this complex is observed in many cancers leading to the selective synthesis of proteins involved in tumour growth and metastasis. The selective translation of cellular mRNAs controlled by this complex also contributes to resistance to cancer treatments, and downregulation of the eIF4F complex components can restore sensitivity to various cancer therapies. Here we review the contribution of the eIF4F complex to tumourigenesis with a focus on its role in chemoresistance as well as the promising use of new small molecule inhibitors of the complex, including flavaglines/rocaglates, hippuristanol and pateamine A.

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Rocchetti F, Tran Quang C, Maragno AL, Nguyen J, Lasgi C, Ghysdael J. (2017 Jan 1)

The calcineurin protein phosphatase is dispensable for BCR-ABL-induced B-ALL maintenance, propagation and response to dasatinib.

Leukemia : DOI : 10.1038/leu.2016.269 En savoir plus
Résumé

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Année de publication : 2016

Nathalie Ly, Nadia Elkhatib, Enzo Bresteau, Olivier Piétrement, Mehdi Khaled, Maria M Magiera, Carsten Janke, Eric Le Cam, Andrew D Rutenberg, Guillaume Montagnac (2016 Oct 18)

αTAT1 controls longitudinal spreading of acetylation marks from open microtubules extremities.

Scientific reports : 35624 : DOI : 10.1038/srep35624 En savoir plus
Résumé

Acetylation of the lysine 40 of α-tubulin (K40) is a post-translational modification occurring in the lumen of microtubules (MTs) and is controlled by the α-tubulin acetyl-transferase αTAT1. How αTAT1 accesses the lumen and acetylates α-tubulin there has been an open question. Here, we report that acetylation starts at open ends of MTs and progressively spreads longitudinally from there. We observed acetylation marks at the open ends of in vivo MTs re-growing after a Nocodazole block, and acetylated segments growing in length with time. Bias for MTs extremities was even more pronounced when using non-dynamic MTs extracted from HeLa cells. In contrast, K40 acetylation was mostly uniform along the length of MTs reconstituted from purified tubulin in vitro. Quantitative modelling of luminal diffusion of αTAT1 suggested that the uniform acetylation pattern observed in vitro is consistent with defects in the MT lattice providing lateral access to the lumen. Indeed, we observed that in vitro MTs are permeable to macromolecules along their shaft while cellular MTs are not. Our results demonstrate αTAT1 enters the lumen from open extremities and spreads K40 acetylation marks longitudinally along cellular MTs. This mode of tip-directed microtubule acetylation may allow for selective acetylation of subsets of microtubules.

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C. Boutros C. Mateus E. Routier S. Chouaib C. Libenciuc M. Reigneau I. Girault C. Caramella S. Hibat S. Vagner Y.G. Tao N. Chaput J. Adam J-C. Soria A. Eggermont E. Deutsch C. Robert (2016 Oct 11)

A dose escalation phase 1 study of radiotherapy (RT) in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab (Ipi) in patients (pts) with metastatic melanoma

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Résumé

https://academic.oup.com/annonc/article/27/suppl_6/1117P/2799932

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Soumyananda Chakraborti, Kathiresan Natarajan, Julian Curiel, Carsten Janke, Judy Liu (2016 Oct 1)

The emerging role of the tubulin code: From the tubulin molecule to neuronal function and disease.

Cytoskeleton (Hoboken, N.J.) : DOI : 10.1002/cm.21290 En savoir plus
Résumé

Across different cell types and tissues, microtubules are assembled from highly conserved dimers of α- and β-tubulin. Despite their highly similar structures, microtubules have functional heterogeneity, generated either by the expression of different tubulin genes, encoding distinct isotypes, or by post-translational modifications of tubulin. This genetically encoded and post-translationally generated heterogeneity of tubulin – the ‘tubulin code’ – has the potential to modulate microtubule structure, dynamics, and interactions with associated proteins. The tubulin code is therefore believed to regulate microtubule functions on a cellular and sub-cellular level. This review highlights the importance of the tubulin code for tubulin structure, as well as on microtubule dynamics and functions in neurons. It further summarizes recent developments in the understanding of mutations in tubulin genes, and how they are linked to neurodegenerative and neurodevelopmental disorders. The current advances in the knowledge of the tubulin code on the molecular and the functional level will certainly lead to a better understanding of how complex signaling events control microtubule functions, especially in cells of the nervous system. This article is protected by copyright. All rights reserved.

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