New papers from Professor Baralle's lab

Valacca, C., Bonomi, S., Buratti, E., Pedrotti, S., Baralle, F.E., Sette, C., Ghigna, C., Biamonti, G. Sam68 regulates EMT through alternative splicing-activated NMD of the SF2/ASF proto-oncogene. J. Cell Biol. 191(1), 87-99

doi: 10.1083/jcb.201001073

Abstract: Epithelial-to-mesenchymal transition (EMT) and its reversal (MET) are crucial cell plasticity programs that act during development and tumor metastasis. We have previously shown that the splicing factor and proto-oncogene SF2/ASF impacts EMT/MET through production of a constitutively active splice variant of the Ron proto-oncogene. Using an in vitro model, we now show that SF2/ASF is also regulated during EMT/MET by alternative splicing associated with the nonsense-mediated mRNA decay pathway (AS-NMD). Overexpression and small interfering RNA experiments implicate the splicing regulator Sam68 in AS-NMD of SF2/ASF transcripts and in the choice between EMT/MET programs. Moreover, Sam68 modulation of SF2/ASF splicing appears to be controlled by epithelial cell–derived soluble factors that act through the ERK1/2 signaling pathway to regulate Sam68 phosphorylation. Collectively, our results reveal a hierarchy of splicing factors that integrate splicing decisions into EMT/MET programs in response to extracellular stimuli.

Buratti, E., Chivers, M., Hwang, G., Vorechovsky, I. DBASS3 and DBASS5: databases of aberrant 3’ and 5’ splice sites. 2010. Nucleic Acids Res. (in press)

doi: 10.1093/nar/gkq887

Abstract: DBASS3 and DBASS5 provide comprehensive repositories of new exon boundaries that were induced by pathogenic mutations in human disease genes. Aberrant 5’ and 3’ splice sites were activated either by mutations in the consensus sequences of natural exon-intron junctions (cryptic sites) or elsewhere (‘de novo’ sites). DBASS3 and DBASS5 currently contain ~900 records of cryptic and de novo 3’ and 5’ splice sites that were produced by over a thousand different mutations in ~360 genes. DBASS3 and DBASS5 data can be searched by disease phenotype, gene, mutation, location of aberrant splice sites in introns and exons and their distance from authentic counterparts, by bibliographic references and by the splice-site strength that was estimated with several prediction algorithms. The user can also retrieve reference sequences of both aberrant and authentic splice sites with the underlying mutation. These data will facilitate identification of introns or exons frequently involved in aberrant splicing, mutation analysis of human disease genes and study of germline or somatic mutations that impair RNA processing. Finally, this resource will be useful for fine-tuning splice-site prediction algorithms, better definition of auxiliary splicing signals and design of new reporter assays. DBASS3 and DBASS5 are freely available at http://www.dbass.org.uk/.