Abstract
The TAF6δ pathway of apoptosis can dictate life versus death decisions independently of the status of p53 tumor suppressor. TAF6δ is an inducible pro-apoptotic subunit of the general RNA polymerase II (Pol II) transcription factor TFIID. Alternative splice site choice of TAF6δ has been shown to be a pivotal event in triggering death via the TAF6δ pathway, yet nothing is currently known about the mechanisms that promote TAF6δ splicing. Furthermore the transcriptome impact of the gain of function of TAF6δ versus the loss of function of the major TAF6α splice form remains undefined. Here we employ comparative microarray analysis to show that TAF6δ drives a transcriptome profile distinct from that resulting from depletion of TAF6α. To define the cis-acting RNA elements responsible for TAF6δ alternative splicing we performed a mutational analysis of a TAF6 minigene system. The data point to several new RNA elements that can modulate TAF6δ and also reveal a role for RNA secondary structure in the selection of TAF6δ.
Highlights
The TAF6d pathway of apoptosis (Fig. S1) can control cell death versus life decisions of human cells [1,2,3]
The minor TAF6d protein isoform is not expressed at detectable levels in HeLa cells under normal growth conditions, so that the effects of the siRNA cannot be due to significant reductions in TAF6d protein levels [2,3]. siRNAs were designed and validated for their ability to reduce TAF6 protein levels
Total RNA was isolated from HeLa cells treated with siRNA directed against TAF6 and from cells treated with control siRNA for microarray analysis [2,22,32]
Summary
The TAF6d pathway of apoptosis (Fig. S1) can control cell death versus life decisions of human cells [1,2,3]. TFIID is the major core promoter recognition complex of the Pol II machinery and consists of TATA-binding protein (TBP) and a constellation of approximately 14 TBP-associated factors (TAFs) [7]. TAF6d is an inducible pro-apoptotic isoform of TAF6 that lacks 10 amino acids in its histone-fold domain. In contrast to the major TAF6a isoform, TAF6d cannot interact with TAF9 and instead forms a TAF9-lacking complex termed TFIIDp that drives a pro-apoptotic gene expression [2]. Because the TAF6d pathway induces cell death independently of p53 [3], it represents a potential therapeutic target of strategic value for the killing of tumor cells that frequently lack functional p53 [8]
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