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Team Publications RNA Biology linked to DNA damage Year of publication 2010 Tony Durand, Gaëtana Di Liberto, Hélène Colman, Anne Cammas, Sebastien Boni, Patrick Marcellin, Annie Cahour, Stephan Vagner, Cyrille Féray (2010 Jul 1) Occult infection of peripheral B cells by hepatitis C variants which have low translational efficiency in cultured hepatocytes. Gut : 934-42 : DOI : 10.1136/gut.2009.192088 Summary Plasma hepatitis C virus (HCV) originates from hepatocytes. However, in certain subjects, B cells may harbour both plasma strains and occult HCV strains tha t are not detected in the plasma. The internal ribosome entry site (IRES) of these latter strains is mutated, suggesting that the efficiency of viral translation could drive the cellular tropism of HCV. Stefania Millevoi, Stéphan Vagner (2010 May 1) Molecular mechanisms of eukaryotic pre-mRNA 3′ end processing regulation. Nucleic acids research : 2757-74 : DOI : 10.1093/nar/gkp1176 Summary Messenger RNA (mRNA) 3′ end formation is a nuclear process through which all eukaryotic primary transcripts are endonucleolytically cleaved and most of them acquire a poly(A) tail. This process, which consists in the recognition of defined poly(A) signals of the pre-mRNAs by a large cleavage/polyadenylation machinery, plays a critical role in gene expression. Indeed, the poly(A) tail of a mature mRNA is essential for its functions, including stability, translocation to the cytoplasm and translation. In addition, this process serves as a bridge in the network connecting the different transcription, capping, splicing and export machineries. It also participates in the quantitative and qualitative regulation of gene expression in a variety of biological processes through the selection of single or alternative poly(A) signals in transcription units. A large number of protein factors associates with this machinery to regulate the efficiency and specificity of this process and to mediate its interaction with other nuclear events. Here, we review the eukaryotic 3′ end processing machineries as well as the comprehensive set of regulatory factors and discuss the different molecular mechanisms of 3′ end processing regulation by proposing several overlapping models of regulation. Martin Dutertre, Magali Lacroix-Triki, Keltouma Driouch, Pierre de la Grange, Lise Gratadou, Samantha Beck, Stefania Millevoi, Jamal Tazi, Rosette Lidereau, Stephan Vagner, Didier Auboeuf (2010 Feb 1) Exon-based clustering of murine breast tumor transcriptomes reveals alternative exons whose expression is associated with metastasis. Cancer research : 896-905 : DOI : 10.1158/0008-5472.CAN-09-2703 INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1 Team Publications RNA Biology linked to DNA damage Summary In the field of bioinformatics, exon profiling is a developing area of disease-associated transcriptome analysis. In this study, we performed a microarray-based transcriptome analysis at the single exon level in mouse 4T1 primary mammary tumors with different metastatic capabilities. A novel bioinformatics platform was developed that identified 679 genes with differentially expressed exons in 4T1 tumors, many of which were involved in cell morphology and movement. Of 152 alternative exons tested by reverse transcription-PCR, 97 were validated as differentially expressed in primary tumors with different metastatic capability. This analysis revealed candidate progression genes, hinting at variations in protein functions by alternate exon usage. In a parallel effort, we developed a novel exonbased clustering analysis and identified alternative exons in tumor transcriptomes that were associated with dissemination of primary tumor cells to sites of pulmonary metastasis. This analysis also revealed that the splicing events identified by comparing primary tumors were not aberrant events. Lastly, we found that a subset of differentially spliced variant transcripts identified in the murine model was associated with poor prognosis in a large clinical cohort of patients with breast cancer. Our findings illustrate the utility of exon profiling to define novel theranostic markers for study in cancer progression and metastasis. Year of publication 2009 Gérard Maillot, Magali Lacroix-Triki, Sandra Pierredon, Lise Gratadou, Sabine Schmidt, Vladimir Bénès, Henri Roché, Florence Dalenc, Didier Auboeuf, Stefania Millevoi, Stéphan Vagner (2009 Nov 1) Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth. Cancer research : 8332-40 : DOI : 10.1158/0008-5472.CAN-09-2206 Summary Altered expression of microRNAs (miRNA), an abundant class of small nonprotein-coding RNAs that mostly function as negative regulators of protein-coding gene expression, is common in cancer. Here, we analyze the regulation of miRNA expression in response to estrogen, a steroid hormone that is involved in the development and progression of breast carcinomas and that is acting via the estrogen receptors (ER) transcription factors. We set out to thoroughly describe miRNA expression, by using miRNA microarrays and real-time reverse transcription-PCR (RT-PCR) experiments, in various breast tumor cell lines in which estrogen signaling has been induced by 17beta-estradiol (E(2)). We show that the expression of a broad set of miRNAs decreases following E(2) treatment in an ER-dependent manner. We further show that enforced expression of several of the repressed miRNAs reduces E(2)dependent cell growth, thus linking expression of specific miRNAs with estrogen-dependent cellular response. In addition, a transcriptome analysis revealed that the E(2)-repressed miR-26a and miR-181a regulate many genes associated with cell growth and proliferation, including the progesterone receptor gene, a key actor in estrogen signaling. Strikingly, miRNA expression is also regulated in breast cancers of women who had received antiestrogen neoadjuvant therapy. Overall, our data indicate that the extensive alterations in INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2 Team Publications RNA Biology linked to DNA damage miRNA regulation upon estrogen signaling pathway play a key role in estrogen-dependent functions and highlight the utility of considering miRNA expression in the understanding of antiestrogen resistance of breast cancer. INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3