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

Proceedings of the National Academy of Sciences of the United States of America
Shuo ChenXin Lu

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...Continue Reading

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Citations

Aug 17, 2020·Nucleic Acids Research·Morgan A SammonsMartin Fischer
Nov 1, 2020·Acta Biochimica Et Biophysica Sinica·Timur YagudinZhenwei Pan
Nov 17, 2020·The FEBS Journal·Françoise S Howe, Xin Lu
May 1, 2021·Cancers·Magdalena C Liebl, Thomas G Hofmann

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Methods Mentioned

BETA
acetylation
immunoprecipitation
RNA-seq
ChIP-seq
ChIP
pull down
Pull-down
nuclear magnetic resonance
size exclusion chromatography

Software Mentioned

WebLogo
iASPP
Genome Browser

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