RBM5/Luca-15/H37 regulates Fas alternative splice site pairing after exon definition.
RBM5/Luca-15/H37 is a gene frequently inactivated in lung cancers and overexpressed in breast tumors. Its protein product has been detected in prespliceosomal complexes and modulates cell proliferation and Fas-mediated apoptosis. We report that RBM5 is a component of complexes involved in 3' splice site recognition and regulates alternative splicing of apoptosis-related genes, including the Fas receptor, switching between isoforms with antagonistic functions in programmed cell death. In contrast with classical mechanisms of splicing regulation, RBM5 does not affect early events of splice site recognition that lead to Fas exon 6 definition. Instead, RBM5 inhibits the transition between prespliceosomal complexes assembled around exon 6 to mature spliceosomes assembled on the flanking introns and promotes sequence-specific pairing of the distal splice sites. An OCRE domain important for RBM5 function contacts components of the U4/5/6 tri-snRNP, consistent with the idea that RBM5 modulates splice site pairing after prespliceosome assembly and exon definition.
Centre de Regulació Genòmica, Dr. Aigüader, 88 08003 Barcelona, Spain.
Sophie
S
Bonnal
Concepción
C
Martínez
Patrik
P
Förch
Angela
A
Bachi
Matthias
M
Wilm
Juan
J
Valcárcel
D017398:Alternative Splicing; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005091:Exons; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007438:Introns; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D022821:RNA Splice Sites; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D000072668:Splicing Factor U2AF; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C491901:FAS protein, human; D009687:Nuclear Proteins; C473448:RBM5 protein, human; D022821:RNA Splice Sites; D016601:RNA-Binding Proteins; D017415:Ribonucleoprotein, U5 Small Nuclear; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; D025521:Tumor Suppressor Proteins; C000607494:U2AF2 protein, human; D019014:fas Receptor; D004247:DNA