The apoptosis-promoting factor TIA-1 is a regulator of alternative pre-mRNA splicing

• Published in: Molecular cell 2000-11, Vol.6 (5), p.1089-1098
• Main Authors: Förch, P, Puig, O, Kedersha, N, Martínez, C, Granneman, S, Séraphin, B, Anderson, P, Valcárcel, J
• Format: Article
• Language: English
• Subjects: Alternative Splicing - genetics; Animals; Apoptosis; Base Sequence; Binding Sites; Conserved Sequence; DNA-Binding Proteins; Drosophila melanogaster; Drosophila melanogaster - genetics; Drosophila Proteins; Fas antigen; fas Receptor - genetics; Fibroblasts; Fungal Proteins - chemistry; Fungal Proteins - metabolism; HeLa Cells; Humans; Introns - genetics; male-specific lethal 2 (msl-2) gene; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Nam8 protein; Nuclear Proteins - genetics; Poly(A)-Binding Proteins; Protein Binding; Proteins; Ribonuclease H - metabolism; Ribonucleoprotein, U1 Small Nuclear - metabolism; Ribonucleoproteins - metabolism; Ribonucleoproteins, Small Nuclear; RNA Precursors - chemistry; RNA Precursors - genetics; RNA Precursors - metabolism; RNA Splice Sites - genetics; RNA, Messenger - chemistry; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - metabolism; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Splicing Factor U2AF; Substrate Specificity; T-Cell Intracellular Antigen-1; TIA-1 protein; Transcription Factors - genetics
• ISSN: 1097-2765
• DOI: 10.1016/s1097-2765(00)00107-6

We report here that the apoptosis-promoting protein TIA-1 regulates alternative pre-mRNA splicing of the Drosophila melanogaster gene male-specific-lethal 2 and of the human apoptotic gene Fas. TIA-1 associates selectively with pre-mRNAs that contain 5' splice sites followed by U-rich sequences. TIA-1 binding to the U-rich stretches facilitates 5' splice site recognition by U1 snRNP. This activity is critical for activation of the weak 5' splice site of msl-2 and for modulating the choice of splice site partner in Fas. Structural and functional similarities with the Saccharomyces cerevisiae splicing factor Nam8 suggest striking evolutionary conservation of a mechanism of pre-mRNA splicing regulation that controls biological processes as diverse as meiosis in yeast, dosage compensation in fruit flies, or programmed cell death in humans.