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

We report here that the apoptosis-promoting protein TIA-1 regulates alterna tive pre-mRNA splicing of the Drosophila melanogaster gene male-specific-le thal 2 and of the human apoptotic gene Fas. TIA-1 associates selectively wi th 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 b y 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 sp licing factor Nam8 suggest striking evolutionary conservation of a mechanis m of pre-mRNA splicing regulation that controls biological processes as div erse as meiosis in yeast, dosage compensation in fruit flies, or programmed cell death in humans.