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iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition
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 incomple...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717262/ https://www.ncbi.nlm.nih.gov/pubmed/31395738 http://dx.doi.org/10.1073/pnas.1909393116 |
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author | Chen, Shuo Wu, Jiale Zhong, Shan Li, Yuntong Zhang, Ping Ma, Jingyi Ren, Jingshan Tan, Yun Wang, Yunhao Au, Kin Fai Siebold, Christian Bond, Gareth L. Chen, Zhu Lu, Min Jones, E. Yvonne Lu, Xin |
author_facet | Chen, Shuo Wu, Jiale Zhong, Shan Li, Yuntong Zhang, Ping Ma, Jingyi Ren, Jingshan Tan, Yun Wang, Yunhao Au, Kin Fai Siebold, Christian Bond, Gareth L. Chen, Zhu Lu, Min Jones, E. Yvonne Lu, Xin |
author_sort | Chen, Shuo |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6717262 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-67172622019-09-13 iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition Chen, Shuo Wu, Jiale Zhong, Shan Li, Yuntong Zhang, Ping Ma, Jingyi Ren, Jingshan Tan, Yun Wang, Yunhao Au, Kin Fai Siebold, Christian Bond, Gareth L. Chen, Zhu Lu, Min Jones, E. Yvonne Lu, Xin Proc Natl Acad Sci U S A PNAS Plus 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. National Academy of Sciences 2019-08-27 2019-08-08 /pmc/articles/PMC6717262/ /pubmed/31395738 http://dx.doi.org/10.1073/pnas.1909393116 Text en Copyright © 2019 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | PNAS Plus Chen, Shuo Wu, Jiale Zhong, Shan Li, Yuntong Zhang, Ping Ma, Jingyi Ren, Jingshan Tan, Yun Wang, Yunhao Au, Kin Fai Siebold, Christian Bond, Gareth L. Chen, Zhu Lu, Min Jones, E. Yvonne Lu, Xin iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition |
title | iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition |
title_full | iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition |
title_fullStr | iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition |
title_full_unstemmed | iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition |
title_short | iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition |
title_sort | iaspp mediates p53 selectivity through a modular mechanism fine-tuning dna recognition |
topic | PNAS Plus |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717262/ https://www.ncbi.nlm.nih.gov/pubmed/31395738 http://dx.doi.org/10.1073/pnas.1909393116 |
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