par Rosewick, Nicolas ;Momont, Mélanie;Durkin, Keith ;Takeda, Haruko;Caiment, Florian;Georges, Michel;Van Den Broeke, Anne ;Cleuter, Yvette ;Burny, Arsène ;Vernin, Céline;Mortreux, Franck;Wattel, Eric
Référence Proceedings of the National Academy of Sciences of the United States of America, 110, 6, page (2306-2311)
Publication Publié, 2013-02
Référence Proceedings of the National Academy of Sciences of the United States of America, 110, 6, page (2306-2311)
Publication Publié, 2013-02
Article révisé par les pairs
Résumé : | Viral tumor models have significantly contributed to our understanding of oncogenic mechanisms. How transforming delta-retroviruses induce malignancy, however, remains poorly understood, especially as viral mRNA/protein are tightly silenced in tumors. Here, using deep sequencing of broad windows of small RNA sizes in the bovine leukemia virus ovine model of leukemia/lymphoma, we provide in vivo evidence of the production of noncanonical RNA polymerase III (Pol III)-transcribed viral microRNAs in leukemic B cells in the complete absence of Pol II 5′-LTR-driven transcriptional activity. Processed from a cluster of five independent self-sufficient transcriptional units located in a proviral region dispensable for in vivo infectivity, bovine leukemia virus microRNAs represent ~40% of all microRNAs in both experimental and natural malignancy. They are subject to strong purifying selection and associate with Argonautes, consistent with a critical function in silencing of important cellular and/or viral targets. Bovine leukemia virus microRNAs are strongly expressed in preleukemic and malignant cells in which structural and regulatory gene expression is repressed, suggesting a key role in tumor onset and progression. Understanding how Pol III-dependent microRNAs subvert cellular and viral pathways will contribute to deciphering the intricate perturbations that underlie malignant transformation. |