Abstract
The tumor suppressor p53 protein activates expression of a vast gene network in response to stress stimuli for cellular integrity. The molecular mechanism underlying how p53 targets RNA polymerase II (Pol II) to regulate transcription remains unclear. To elucidate the p53/Pol II interaction, we have determined a 4.6 Å resolution structure of the human p53/Pol II assembly via single particle cryo-electron microscopy. Our structure reveals that p53’s DNA binding domain targets the upstream DNA binding site within Pol II. This association introduces conformational changes of the Pol II clamp into a further-closed state. A cavity was identified between p53 and Pol II that could possibly host DNA. The transactivation domain of p53 binds the surface of Pol II’s jaw that contacts downstream DNA. These findings suggest that p53’s functional domains directly regulate DNA binding activity of Pol II to mediate transcription, thereby providing insights into p53-regulated gene expression.
Highlights
The tumor suppressor p53 protein activates expression of a vast gene network in response to stress stimuli for cellular integrity
The human p53 protein is a potent transcriptional activator that turns on diverse gene expression programs to regulate cellular processes for tumor inhibition11,12. p53 is promptly activated upon various stress signals that include DNA damage, oncogene activation and hypoxia[12]
Biochemical studies have shown that p53 binds consensus sequences on target gene promoters to directly turn on transcription14. p53 can directly bind and recruit several components of the pre-initiation complex (PIC) (e.g., Mediator, TFIIB, TFIID, TFIIH) to synergistically promote the assembly on the promoter[15,16,17,18,19,20,21]
Summary
The tumor suppressor p53 protein activates expression of a vast gene network in response to stress stimuli for cellular integrity. Our structure reveals that p53’s DNA binding domain targets the upstream DNA binding site within Pol II This association introduces conformational changes of the Pol II clamp into a further-closed state. In addition to transcription initiation, our recent work demonstrates that the interaction of p53 and Pol II directly enhances the elongation efficiency of Pol II22 These activities could be attributed to p53’s ability to structurally regulate target co-factors. Our recent structural work reveal that the p53/Pol II association permits the Pol II DNA-binding clamp to adopt a closed state[22] These studies suggest that the interaction between p53 and its target factors introduce specific structural features that could help direct transcription activation.
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