Structural visualization of the p53/RNA polymerase II assembly

The master tumor suppressor p53 activates transcription in response to various cellular stresses, in part by facilitating recruitment of the transcription machinery to DNA. Recent studies have documented a direct, yet poorly characterized interaction between p53 and RNA Polymerase II (Pol II). Therefore, we have dissected the human p53/Pol II interaction via single particle cryo-electron microscopy, structural docking and biochemical analyses. This study reveals that p53 binds Pol II via the Rpb1 and Rpb2 subunits, bridging the DNA binding cleft of Pol II proximal to the upstream DNA entry site. In addition, the key DNA binding surface of p53, frequently disrupted in various cancers, remains exposed within the assembly. This suggests that p53 may retain its ability to bind DNA when associated with Pol II. Furthermore, the p53/Pol II co-complex displays a closed conformation as defined by position of the Pol II clamp domain. Notably, the interaction of p53 and Pol II leads to increased Pol II elongation activity. These findings indicate that p53 may structurally regulate DNA binding functions of Pol II via the clamp domain, thereby providing insights on p53-regulated Pol II transcription.