Quaternary structure of the specific p53–DNA complex reveals the mechanism of p53 mutant dominance

The p53 tumour suppressor is a transcriptional activator that controls cell fate in response to various stresses. p53 can initiate cell cycle arrest, senescence and/or apoptosis via transactivation of p53 target genes, thus preventing cancer onset. Mutations that impair p53 usually occur in the core...

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Main Authors:	Aramayo, Ricardo, Sherman, Michael B., Brownless, Kathryne, Lurz, Rudi, Okorokov, Andrei L., Orlova, Elena V.
Format:	Online
Language:	English
Published:	Oxford University Press 2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203597/

id	pubmed-3203597
recordtype	oai_dc
spelling	pubmed-32035972011-10-28 Quaternary structure of the specific p53–DNA complex reveals the mechanism of p53 mutant dominance Aramayo, Ricardo Sherman, Michael B. Brownless, Kathryne Lurz, Rudi Okorokov, Andrei L. Orlova, Elena V. Structural Biology The p53 tumour suppressor is a transcriptional activator that controls cell fate in response to various stresses. p53 can initiate cell cycle arrest, senescence and/or apoptosis via transactivation of p53 target genes, thus preventing cancer onset. Mutations that impair p53 usually occur in the core domain and negate the p53 sequence-specific DNA binding. Moreover, these mutations exhibit a dominant negative effect on the remaining wild-type p53. Here, we report the cryo electron microscopy structure of the full-length p53 tetramer bound to a DNA-encoding transcription factor response element (RE) at a resolution of 21 Å. While two core domains from both dimers of the p53 tetramer interact with DNA within the complex, the other two core domains remain available for binding another DNA site. This finding helps to explain the dominant negative effect of p53 mutants based on the fact that p53 dimers are formed co-translationally before the whole tetramer assembles; therefore, a single mutant dimer would prevent the p53 tetramer from binding DNA. The structure indicates that the Achilles’ heel of p53 is in its dimer-of-dimers organization, thus the tetramer activity can be negated by mutation in only one allele followed by tumourigenesis. Oxford University Press 2011-11 2011-07-15 /pmc/articles/PMC3203597/ /pubmed/21764777 http://dx.doi.org/10.1093/nar/gkr386 Text en © The Author(s) 2011. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Aramayo, Ricardo Sherman, Michael B. Brownless, Kathryne Lurz, Rudi Okorokov, Andrei L. Orlova, Elena V.
spellingShingle	Aramayo, Ricardo Sherman, Michael B. Brownless, Kathryne Lurz, Rudi Okorokov, Andrei L. Orlova, Elena V. Quaternary structure of the specific p53–DNA complex reveals the mechanism of p53 mutant dominance
author_facet	Aramayo, Ricardo Sherman, Michael B. Brownless, Kathryne Lurz, Rudi Okorokov, Andrei L. Orlova, Elena V.
author_sort	Aramayo, Ricardo
title	Quaternary structure of the specific p53–DNA complex reveals the mechanism of p53 mutant dominance
title_short	Quaternary structure of the specific p53–DNA complex reveals the mechanism of p53 mutant dominance
title_full	Quaternary structure of the specific p53–DNA complex reveals the mechanism of p53 mutant dominance
title_fullStr	Quaternary structure of the specific p53–DNA complex reveals the mechanism of p53 mutant dominance
title_full_unstemmed	Quaternary structure of the specific p53–DNA complex reveals the mechanism of p53 mutant dominance
title_sort	quaternary structure of the specific p53–dna complex reveals the mechanism of p53 mutant dominance
description	The p53 tumour suppressor is a transcriptional activator that controls cell fate in response to various stresses. p53 can initiate cell cycle arrest, senescence and/or apoptosis via transactivation of p53 target genes, thus preventing cancer onset. Mutations that impair p53 usually occur in the core domain and negate the p53 sequence-specific DNA binding. Moreover, these mutations exhibit a dominant negative effect on the remaining wild-type p53. Here, we report the cryo electron microscopy structure of the full-length p53 tetramer bound to a DNA-encoding transcription factor response element (RE) at a resolution of 21 Å. While two core domains from both dimers of the p53 tetramer interact with DNA within the complex, the other two core domains remain available for binding another DNA site. This finding helps to explain the dominant negative effect of p53 mutants based on the fact that p53 dimers are formed co-translationally before the whole tetramer assembles; therefore, a single mutant dimer would prevent the p53 tetramer from binding DNA. The structure indicates that the Achilles’ heel of p53 is in its dimer-of-dimers organization, thus the tetramer activity can be negated by mutation in only one allele followed by tumourigenesis.
publisher	Oxford University Press
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203597/
_version_	1611484264211152896

Quaternary structure of the specific p53–DNA complex reveals the mechanism of p53 mutant dominance

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