Cooperativity dominates the genomic organization of p53-response elements: a mechanistic view.

p53-response elements (p53-REs) are organized as two repeats of a palindromic DNA segment spaced by 0 to 20 base pairs (bp). Several experiments indicate that in the vast majority of the human p53-REs there are no spacers between the two repeats; those with spacers, particularly with sizes beyond tw...

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Autores principales:	Yongping Pan, Ruth Nussinov
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/a787ec909db64729904d831aed0305f0
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spelling	oai:doaj.org-article:a787ec909db64729904d831aed0305f02021-11-25T05:42:16ZCooperativity dominates the genomic organization of p53-response elements: a mechanistic view.1553-734X1553-735810.1371/journal.pcbi.1000448https://doaj.org/article/a787ec909db64729904d831aed0305f02009-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19629163/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358p53-response elements (p53-REs) are organized as two repeats of a palindromic DNA segment spaced by 0 to 20 base pairs (bp). Several experiments indicate that in the vast majority of the human p53-REs there are no spacers between the two repeats; those with spacers, particularly with sizes beyond two nucleotides, are rare. This raises the question of what it indicates about the factors determining the p53-RE genomic organization. Clearly, given the double helical DNA conformation, the orientation of two p53 core domain dimers with respect to each other will vary depending on the spacer size: a small spacer of 0 to 2 bps will lead to the closest p53 dimer-dimer orientation; a 10-bp spacer will locate the p53 dimers on the same DNA face but necessitate DNA looping; while a 5-bp spacer will position the p53 dimers on opposite DNA faces. Here, via conformational analysis we show that when there are 0-2 bp spacers, p53-DNA binding is cooperative; however, cooperativity is greatly diminished when there are spacers with sizes beyond 2 bp. Cooperative binding is broadly recognized to be crucial for biological processes, including transcriptional regulation. Our results clearly indicate that cooperativity of the p53-DNA association dominates the genomic organization of the p53-REs, raising questions of the structural organization and functional roles of p53-REs with larger spacers. We further propose that a dynamic landscape scenario of p53 and p53-REs can better explain the selectivity of the degenerate p53-REs. Our conclusions bear on the evolutionary preference of the p53-RE organization and as such, are expected to have broad implications to other multimeric transcription factor response element organization.Yongping PanRuth NussinovPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 5, Iss 7, p e1000448 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Yongping Pan Ruth Nussinov Cooperativity dominates the genomic organization of p53-response elements: a mechanistic view.
description	p53-response elements (p53-REs) are organized as two repeats of a palindromic DNA segment spaced by 0 to 20 base pairs (bp). Several experiments indicate that in the vast majority of the human p53-REs there are no spacers between the two repeats; those with spacers, particularly with sizes beyond two nucleotides, are rare. This raises the question of what it indicates about the factors determining the p53-RE genomic organization. Clearly, given the double helical DNA conformation, the orientation of two p53 core domain dimers with respect to each other will vary depending on the spacer size: a small spacer of 0 to 2 bps will lead to the closest p53 dimer-dimer orientation; a 10-bp spacer will locate the p53 dimers on the same DNA face but necessitate DNA looping; while a 5-bp spacer will position the p53 dimers on opposite DNA faces. Here, via conformational analysis we show that when there are 0-2 bp spacers, p53-DNA binding is cooperative; however, cooperativity is greatly diminished when there are spacers with sizes beyond 2 bp. Cooperative binding is broadly recognized to be crucial for biological processes, including transcriptional regulation. Our results clearly indicate that cooperativity of the p53-DNA association dominates the genomic organization of the p53-REs, raising questions of the structural organization and functional roles of p53-REs with larger spacers. We further propose that a dynamic landscape scenario of p53 and p53-REs can better explain the selectivity of the degenerate p53-REs. Our conclusions bear on the evolutionary preference of the p53-RE organization and as such, are expected to have broad implications to other multimeric transcription factor response element organization.
format	article
author	Yongping Pan Ruth Nussinov
author_facet	Yongping Pan Ruth Nussinov
author_sort	Yongping Pan
title	Cooperativity dominates the genomic organization of p53-response elements: a mechanistic view.
title_short	Cooperativity dominates the genomic organization of p53-response elements: a mechanistic view.
title_full	Cooperativity dominates the genomic organization of p53-response elements: a mechanistic view.
title_fullStr	Cooperativity dominates the genomic organization of p53-response elements: a mechanistic view.
title_full_unstemmed	Cooperativity dominates the genomic organization of p53-response elements: a mechanistic view.
title_sort	cooperativity dominates the genomic organization of p53-response elements: a mechanistic view.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/a787ec909db64729904d831aed0305f0
work_keys_str_mv	AT yongpingpan cooperativitydominatesthegenomicorganizationofp53responseelementsamechanisticview AT ruthnussinov cooperativitydominatesthegenomicorganizationofp53responseelementsamechanisticview
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Cooperativity dominates the genomic organization of p53-response elements: a mechanistic view.

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