title: Oxidative stress controls the choice of alternative last exons via a Brahma-BRCA1-CstF pathway.
abstract: Alternative splicing of terminal exons increases transcript and protein diversity. How physiological and pathological stimuli regulate the choice between alternative terminal exons is, however, largely unknown. Here, we show that Brahma (BRM), the ATPase subunit of the hSWI/SNF chromatin-remodeling complex interacts with BRCA1/BARD1, which ubiquitinates the 50 kDa subunit of the 3' end processing factor CstF. This results in the inhibition of transcript cleavage at the proximal poly(A) site and a shift towards inclusion of the distal terminal exon. Upon oxidative stress, BRM is depleted, cleavage inhibition is released, and inclusion of the proximal last exon is favoored. Our findings elucidate a novel regulatory mechanism, distinct from the modulation of transcription elongation by BRM that controls alternative splicing of internal exons.
authors: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
authors: Gabriele A
authors: GA
authors: Fontana
authors: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
authors: Aurora
authors: A
authors: Rigamonti
authors: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
authors: Silvia C
authors: SC
authors: Lenzken
authors: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
authors: Giuseppe
authors: G
authors: Filosa
authors: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
authors: Reinaldo
authors: R
authors: Alvarez
authors: Department of Biotechnology and Health Sciences, University of Torino, Via Nizza 52, I-10126 Torino, Italy.
authors: Raffaele
authors: R
authors: Calogero
authors: Division of Genetics and Cell Biology, San Raffaele Scientific Institute and University, Via Olgettina 60, 20132 Milan, Italy.
authors: Marco E
authors: ME
authors: Bianchi
authors: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy silvia.barabino@unimib.it.
authors: Silvia M L
authors: SM
authors: Barabino
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D017398:Alternative Splicing; D019313:BRCA1 Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D039241:Cleavage Stimulation Factor / Q000378:metabolism*; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D046912:Multiprotein Complexes; D018384:Oxidative Stress / Q000235:genetics; D011061:Poly A; D011485:Protein Binding; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D019313:BRCA1 Protein; D039241:Cleavage Stimulation Factor; D046912:Multiprotein Complexes; C084011:SMARCA2 protein, human; D014157:Transcription Factors; D011061:Poly A; D000251:Adenosine Triphosphatases