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


ABSTRACT: 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.

SUBMITTER: Chen S 

PROVIDER: S-EPMC6717262 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Chen Shuo S   Wu Jiale J   Zhong Shan S   Li Yuntong Y   Zhang Ping P   Ma Jingyi J   Ren Jingshan J   Tan Yun Y   Wang Yunhao Y   Au Kin Fai KF   Siebold Christian C   Bond Gareth L GL   Chen Zhu Z   Lu Min M   Jones E Yvonne EY   Lu Xin X  

Proceedings of the National Academy of Sciences of the United States of America 20190808 35


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  ...[more]

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