Cancer-controlling p53 genetic regulatory network: Arrangements of p53 tetramer following different DNA instructions. Are you positive?

Abstract: The p53 protein operates as a tumor suppressor and regulates hundreds of genes through p53 network. At least 50% cancers are related to the inactivation of p53 due to p53 mutation. A crucial question is how p53 protein differentiates between hundreds of p53 response elements (p53REs) to function properly. With results obtained from several computational approches, an emerging picture suggests that p53 may use multiple binding modes to perform its complicated task. (I)Analysis of potential p53REs in human genome revealed the DNA symmetries in p53REs encode the p53 binding modes, which differ substantially in positive regulations and negative regulations. (II) Structural analysis of available p53-DNA complex structures identified possible protein-protein and protein-DNA interfaces in p53-DNA recognization. (III) Explorations of p53-DNA interactions for multiple sequences using 30 Molecular dynamics simulations provided a comprehensive modeling of possible p53-DNA binding modes. (IV) Conformational energy evaluations using reconstructed energy landscape connecting possible binding modes. The converged computational results are consistent with experimental evidences and explain p53’s ability to recognize DNA in both sequence-specific and geometry- specific ways. More challenges remain to understand the consequences of p53 mutation within the framework of p53 systems biology.