The spliceosome as a target of novel antitumour drugs
ABSTRACT Several bacterial fermentation products and their synthetic derivatives display antitumour activities and bind tightly to components of the spliceosome, which is the complex molecular machinery involved in the removal of introns from mRNA precursors in eukaryotic cells. The drugs alter gene expression, including alternative splicing, of genes that are important for cancer progression. A flurry of recent reports has revealed that genes encoding splicing factors, including the drug target splicing factor 3B subunit 1 (SF3B1), are among the most highly mutated in various haematological malignancies such as chronic lymphocytic leukaemia and myelodysplastic syndromes. These observations highlight the role of splicing factors in cancer and suggest that an understanding of the molecular effects of drugs targeting these proteins could open new perspectives for studies of the spliceosome and its role in cancer progression, and for the development of novel antitumour therapies.
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ABSTRACT: Pre-mRNA splicing relies on the poorly understood dynamic interplay between >150 protein components of the spliceosome. The steps at which splicing can be regulated remain largely unknown. We systematically analyzed the effect of knocking down the components of the splicing machinery on alternative splicing events relevant for cell proliferation and apoptosis and used this information to reconstruct a network of functional interactions. The network accurately captures known physical and functional associations and identifies new ones, revealing remarkable regulatory potential of core spliceosomal components, related to the order and duration of their recruitment during spliceosome assembly. In contrast with standard models of regulation at early steps of splice site recognition, factors involved in catalytic activation of the spliceosome display regulatory properties. The network also sheds light on the antagonism between hnRNP C and U2AF, and on targets of antitumor drugs, and can be widely used to identify mechanisms of splicing regulationMolecular Cell 01/2015; DOI:10.1016/j.molcel.2014.10.030 · 14.46 Impact Factor
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ABSTRACT: Alternative splicing is a fundamental step in regulation of gene expression of many tumor suppressors and oncogenes in cancer. Signalling through the Ras-MAPK and PI3K-mTOR pathways is misregulated and hyperactivated in most types of cancer. However, the regulation of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing is less well established. Recent studies have shown the contribution of alternative splicing regulation of these signalling pathways which can lead to cellular transformation, cancer development, and tumor maintenance. This review will discuss findings in the literature which describe new modes of regulation of components of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing. We will also describe the mechanisms by which signals from extracellular stimuli can be communicated to the splicing machinery and to specific RNA-binding proteins that ultimately control exon definition events.International Journal of Cell Biology 09/2013; 2013:568931. DOI:10.1155/2013/568931
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ABSTRACT: We present a genome-wide analysis of splicing patterns of 282 kidney renal clear cell carcinoma patients in which we integrate data from whole-exome sequencing of tumor and normal samples, RNA-seq and copy number variation. We proposed a scoring mechanism to compare splicing patterns in tumor samples to normal samples in order to rank and detect tumor-specific isoforms that have a potential for new biomarkers. We identified a subset of genes that show introns only observable in tumor but not in normal samples, ENCODE and GEUVADIS samples. In order to improve our understanding of the underlying genetic mechanisms of splicing variation we performed a large-scale association analysis to find links between somatic or germline variants with alternative splicing events. We identified 915 cis- and trans-splicing quantitative trait loci (sQTL) associated with changes in splicing patterns. Some of these sQTL have previously been associated with being susceptibility loci for cancer and other diseases. Our analysis also allowed us to identify the function of several COSMIC variants showing significant association with changes in alternative splicing. This demonstrates the potential significance of variants affecting alternative splicing events and yields insights into the mechanisms related to an array of disease phenotypes.Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing 20:44-55.