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DNA specificities modulate the binding of human transcription factor A to mitochondrial DNA control region

Human mitochondrial DNA (h-mtDNA) codes for 13 subunits of the oxidative phosphorylation pathway, the essential route that produces ATP. H-mtDNA transcription and replication depends on the transcription factor TFAM, which also maintains and compacts this genome. It is well-established that TFAM act...

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Autores principales: Cuppari, Anna, Fernández-Millán, Pablo, Battistini, Federica, Tarrés-Solé, Aleix, Lyonnais, Sébastien, Iruela, Guillermo, Ruiz-López, Elena, Enciso, Yuliana, Rubio-Cosials, Anna, Prohens, Rafel, Pons, Miquel, Alfonso, Carlos, Tóth, Katalin, Rivas, Germán, Orozco, Modesto, Solà, Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614842/
https://www.ncbi.nlm.nih.gov/pubmed/31114891
http://dx.doi.org/10.1093/nar/gkz406
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author Cuppari, Anna
Fernández-Millán, Pablo
Battistini, Federica
Tarrés-Solé, Aleix
Lyonnais, Sébastien
Iruela, Guillermo
Ruiz-López, Elena
Enciso, Yuliana
Rubio-Cosials, Anna
Prohens, Rafel
Pons, Miquel
Alfonso, Carlos
Tóth, Katalin
Rivas, Germán
Orozco, Modesto
Solà, Maria
author_facet Cuppari, Anna
Fernández-Millán, Pablo
Battistini, Federica
Tarrés-Solé, Aleix
Lyonnais, Sébastien
Iruela, Guillermo
Ruiz-López, Elena
Enciso, Yuliana
Rubio-Cosials, Anna
Prohens, Rafel
Pons, Miquel
Alfonso, Carlos
Tóth, Katalin
Rivas, Germán
Orozco, Modesto
Solà, Maria
author_sort Cuppari, Anna
collection PubMed
description Human mitochondrial DNA (h-mtDNA) codes for 13 subunits of the oxidative phosphorylation pathway, the essential route that produces ATP. H-mtDNA transcription and replication depends on the transcription factor TFAM, which also maintains and compacts this genome. It is well-established that TFAM activates the mtDNA promoters LSP and HSP1 at the mtDNA control region where DNA regulatory elements cluster. Previous studies identified still uncharacterized, additional binding sites at the control region downstream from and slightly similar to LSP, namely sequences X and Y (Site-X and Site-Y) (Fisher et al., Cell 50, pp 247–258, 1987). Here, we explore TFAM binding at these two sites and compare them to LSP by multiple experimental and in silico methods. Our results show that TFAM binding is strongly modulated by the sequence-dependent properties of Site-X, Site-Y and LSP. The high binding versatility of Site-Y or the considerable stiffness of Site-X tune TFAM interactions. In addition, we show that increase in TFAM/DNA complex concentration induces multimerization, which at a very high concentration triggers disruption of preformed complexes. Therefore, our results suggest that mtDNA sequences induce non-uniform TFAM binding and, consequently, direct an uneven distribution of TFAM aggregation sites during the essential process of mtDNA compaction.
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spelling pubmed-66148422019-07-12 DNA specificities modulate the binding of human transcription factor A to mitochondrial DNA control region Cuppari, Anna Fernández-Millán, Pablo Battistini, Federica Tarrés-Solé, Aleix Lyonnais, Sébastien Iruela, Guillermo Ruiz-López, Elena Enciso, Yuliana Rubio-Cosials, Anna Prohens, Rafel Pons, Miquel Alfonso, Carlos Tóth, Katalin Rivas, Germán Orozco, Modesto Solà, Maria Nucleic Acids Res Structural Biology Human mitochondrial DNA (h-mtDNA) codes for 13 subunits of the oxidative phosphorylation pathway, the essential route that produces ATP. H-mtDNA transcription and replication depends on the transcription factor TFAM, which also maintains and compacts this genome. It is well-established that TFAM activates the mtDNA promoters LSP and HSP1 at the mtDNA control region where DNA regulatory elements cluster. Previous studies identified still uncharacterized, additional binding sites at the control region downstream from and slightly similar to LSP, namely sequences X and Y (Site-X and Site-Y) (Fisher et al., Cell 50, pp 247–258, 1987). Here, we explore TFAM binding at these two sites and compare them to LSP by multiple experimental and in silico methods. Our results show that TFAM binding is strongly modulated by the sequence-dependent properties of Site-X, Site-Y and LSP. The high binding versatility of Site-Y or the considerable stiffness of Site-X tune TFAM interactions. In addition, we show that increase in TFAM/DNA complex concentration induces multimerization, which at a very high concentration triggers disruption of preformed complexes. Therefore, our results suggest that mtDNA sequences induce non-uniform TFAM binding and, consequently, direct an uneven distribution of TFAM aggregation sites during the essential process of mtDNA compaction. Oxford University Press 2019-07-09 2019-05-22 /pmc/articles/PMC6614842/ /pubmed/31114891 http://dx.doi.org/10.1093/nar/gkz406 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Structural Biology
Cuppari, Anna
Fernández-Millán, Pablo
Battistini, Federica
Tarrés-Solé, Aleix
Lyonnais, Sébastien
Iruela, Guillermo
Ruiz-López, Elena
Enciso, Yuliana
Rubio-Cosials, Anna
Prohens, Rafel
Pons, Miquel
Alfonso, Carlos
Tóth, Katalin
Rivas, Germán
Orozco, Modesto
Solà, Maria
DNA specificities modulate the binding of human transcription factor A to mitochondrial DNA control region
title DNA specificities modulate the binding of human transcription factor A to mitochondrial DNA control region
title_full DNA specificities modulate the binding of human transcription factor A to mitochondrial DNA control region
title_fullStr DNA specificities modulate the binding of human transcription factor A to mitochondrial DNA control region
title_full_unstemmed DNA specificities modulate the binding of human transcription factor A to mitochondrial DNA control region
title_short DNA specificities modulate the binding of human transcription factor A to mitochondrial DNA control region
title_sort dna specificities modulate the binding of human transcription factor a to mitochondrial dna control region
topic Structural Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614842/
https://www.ncbi.nlm.nih.gov/pubmed/31114891
http://dx.doi.org/10.1093/nar/gkz406
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