Bacterial fermentation products with cytostatic and antitumour activity target components of the basal precursor mRNA (pre-mRNA) splicing machinery.
At least some of these drugs achieve their effects by interfering with mechanisms that ensure proper recognition of 3′ splice site sequences by spliceosomal U2 small nuclear ribonucleoprotein (snRNP) particles.
Rather than global inhibition of the splicing process, cytostatic drug concentrations induce changes in alternative pre-mRNA splicing and downregulation of genes important for cell cycle and tumour progression.
The drugs display significantly more potent effects on cancer cells than on normal cells and retain their activity on multidrug-resistant cells.
The drug target splicing factor 3B subunit 1 (SF3B1) is a protein component of U2 snRNP that is frequently mutated in myelodysplasias with ring sideroblasts and in chronic lymphocytic leukaemia.
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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We thank P. Cironi, C. López-Otín, P. Potter, V. Quesada, J. Vilardell, T. Webb and members of our laboratory for discussions and comments on the manuscript, and three anonymous reviewers for useful suggestions. Work in our group has been supported by Fundación Botín, Consolider RNAREG, Ministerio de Economía y Competitividad, AGAUR, AICR and EURASNET.
The authors declare no competing financial interests.
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Bonnal, S., Vigevani, L. & Valcárcel, J. The spliceosome as a target of novel antitumour drugs. Nat Rev Drug Discov 11, 847–859 (2012). https://doi.org/10.1038/nrd3823
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