|Dr. Dvir's Research: Molecular Mechanisms of Gene Transcription|
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Mechanism of Promoter Escape
It is now well-established that promoter binding by RNA polymerase II and transcription factors (“preinitiation complex assembly”) is a critical step in gene transcription. However, emerging new data indicate that post-assembly steps in transcription might be rate-limiting to the process of gene expression. Relatively little is known about these steps, that require detailed biochemical analysis of the transcription complex. In studies that we carried out in a reconstituted transcription system we have demonstrated the existence of a rate-limiting step at the onset of the transcription cycle which we named Promoter Escape. The Promoter Escape stage encompasses the synthesis of the first 14-15 nucleotides of nascent RNA transcripts, during which the RNA polymerase often stalls or completely aborts its transcripts and dissociates from the templates. We have investigated the mechanism of transcription in this early stage and identified a specific requirement for three cofactors - ATP, TFIIH, and downstream DNA. In the absence of either of these cofactors, the polymerase is unable to escape the promoter and continue elongation of nascent transcripts. We have determined that the three cofactors work by a common mechanism which functions continuously through this early stage of transcription. New evidence from other laboratories, based on our findings, indicate that certain regulatory transcription factors specifically control transcription by acting on the activities we have described.
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