The most frequently mutated protein in human cancer is p53, a transcription factor (TF) that regulates myriad genes instrumental in diverse cellular outcomes including growth arrest and cell death. Cell context-dependent p53 modulation is critical for this life-or-death balance, yet remains incompletely understood. Here we identify sequence signatures enriched in genomic p53-binding sites modulated by the transcription cofactor iASPP. Moreover, our p53-iASPP crystal structure reveals that iASPP displaces the p53 L1 loop-which mediates sequence-specific interactions with the signature-corresponding base-without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. A TF commonly uses multiple structural modules to recognize its cognate DNA, and thus this mechanism of a cofactor fine-tuning TF-DNA interactions through targeting a particular module is likely widespread. Previously, all tumor suppressors and oncoproteins that associate with the p53 DNA-binding domain-except the oncogenic E6 from human papillomaviruses (HPVs)-structurally cluster at the DNA-binding site of p53, complicating drug design. By contrast, iASPP inhibits p53 through a distinct surface overlapping the E6 footprint, opening prospects for p53-targeting precision medicine to improve cancer therapy.
Proceedings of the National Academy of Sciences of the United States of America
17470 - 17479
Ludwig Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
Cell Line, Tumor, Humans, Intracellular Signaling Peptides and Proteins, Oncogene Proteins, Viral, Repressor Proteins, DNA, Gene Expression Profiling, Binding Sites, Base Sequence, Response Elements, Protein Conformation, Protein Binding, Structure-Activity Relationship, Models, Molecular, Tumor Suppressor Protein p53, Nucleotide Motifs