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Apoptotic cell death is associated with altered levels of mRNA expression, yet the mechanisms that coordinate changes in gene expression with activation of the cell death machinery remain obscure. Here, we report the cloning and characterization of hTAF(II)80 delta, a specialized isoform of the general transcription factor TFIID subunit hTAF(II)80. Several distinct apoptotic stimuli induce the expression and caspase-dependent cleavage of hTAF(II)80 delta. hTAF(II)80 delta, unlike hTAF(II)80, forms a TFIID-like complex lacking hTAF(II)31. Elevated expression of hTAF(II)80 delta in HeLa cells is sufficient to trigger apoptotic cell death and selectively alters cellular transcription, including the induction of the target genes gadd45 and p21. These data define a signaling pathway that couples apoptotic signals to a reprogramming of RNA polymerase II transcription.