iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

Shuo Chen, Jiale Wu, Shan Zhong, Yuntong Li, Ping Zhang, Jingyi Ma, Jingshan Ren, Yun Tan, Yunhao Wang, Kin Fai Au, Christian Siebold, Gareth L Bond, Zhu Chen, Min Lu, E Yvonne Jones, Xin Lu

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)17470-17479
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number35
Early online date8 Aug 2019
Publication statusPublished - 27 Aug 2019


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