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Alternative splicing : the pledge, the turn, and the prestige : the key role of alternative splicing in human biological systems
Publication . Gallego Páez, Lina Marcela; Bordone, Marie C.; Leote, Ana Carolina; Saraiva-Agostinho, Nuno; Ascensão-Ferreira, Mariana; Barbosa-Morais, Nuno
Alternative pre-mRNA splicing is a tightly controlled process conducted by the spliceosome, with the assistance of several regulators, resulting in the expression of different transcript isoforms from the same gene and increasing both transcriptome and proteome complexity. The differences between alternative isoforms may be subtle but enough to change the function or localization of the translated proteins. A fine control of the isoform balance is, therefore, needed throughout developmental stages and adult tissues or physiological conditions and it does not come as a surprise that several diseases are caused by its deregulation. In this review, we aim to bring the splicing machinery on stage and raise the curtain on its mechanisms and regulation throughout several systems and tissues of the human body, from neurodevelopment to the interactions with the human microbiome. We discuss, on one hand, the essential role of alternative splicing in assuring tissue function, diversity, and swiftness of response in these systems or tissues, and on the other hand, what goes wrong when its regulatory mechanisms fail. We also focus on the possibilities that splicing modulation therapies open for the future of personalized medicine, along with the leading techniques in this field. The final act of the spliceosome, however, is yet to be fully revealed, as more knowledge is needed regarding the complex regulatory network that coordinates alternative splicing and how its dysfunction leads to disease.
The splicing factor XAB2 interacts with ERCC1-XPF and XPG for R-loop processing
Publication . Goulielmaki, Evi; Tsekrekou, Maria; Batsiotos, Nikos; Ascensão-Ferreira, Mariana; Ledaki, Eleftheria; Stratigi, Kalliopi; Chatzinikolaou, Georgia; Topalis, Pantelis; Kosteas, Theodore; Altmüller, Janine; Demmers, Jeroen A.; Barbosa-Morais, Nuno; Garinis, George A.
RNA splicing, transcription and the DNA damage response are intriguingly linked in mammals but the underlying mechanisms remain poorly understood. Using an in vivo biotinylation tagging approach in mice, we show that the splicing factor XAB2 interacts with the core spliceosome and that it binds to spliceosomal U4 and U6 snRNAs and pre-mRNAs in developing livers. XAB2 depletion leads to aberrant intron retention, R-loop formation and DNA damage in cells. Studies in illudin S-treated cells and Csbm/m developing livers reveal that transcription-blocking DNA lesions trigger the release of XAB2 from all RNA targets tested. Immunoprecipitation studies reveal that XAB2 interacts with ERCC1-XPF and XPG endonucleases outside nucleotide excision repair and that the trimeric protein complex binds RNA:DNA hybrids under conditions that favor the formation of R-loops. Thus, XAB2 functionally links the spliceosomal response to DNA damage with R-loop processing with important ramifications for transcription-coupled DNA repair disorders.
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Fundação para a Ciência e a Tecnologia
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IF/00595/2014/CP1236/CT0002