Porphyrin binding mechanism is altered by protonation at the loops in G-quadruplex DNA formed near the transcriptional activation site of the human c-kit gene

Background G-quadruplex DNA structures are hypothesized to be involved in the regulation of gene expression and telomere homeostasis. The development of small molecules that modulate the stability of G-quadruplex structures has a potential therapeutic interest in cancer treatment and prevention of a...

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Autores: Manaye, Sintayehu, Eritja i Casadellà, Ramon, Aviñó Andrés, Anna, Jaumot Soler, Joaquim, Gargallo Gómez, Raimundo
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2012
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/128186
Acceso en línea:https://hdl.handle.net/2445/128186
Access Level:acceso abierto
Palabra clave:Porfirines
Telòmer
Expressió gènica
Oncogens
Porphyrins
Telomere
Gene expression
Oncogenes
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spelling Porphyrin binding mechanism is altered by protonation at the loops in G-quadruplex DNA formed near the transcriptional activation site of the human c-kit geneManaye, SintayehuEritja i Casadellà, RamonAviñó Andrés, AnnaJaumot Soler, JoaquimGargallo Gómez, RaimundoPorfirinesTelòmerExpressió gènicaOncogensPorphyrinsTelomereGene expressionOncogenesBackground G-quadruplex DNA structures are hypothesized to be involved in the regulation of gene expression and telomere homeostasis. The development of small molecules that modulate the stability of G-quadruplex structures has a potential therapeutic interest in cancer treatment and prevention of aging. Methods Molecular absorption and circular dichroism spectra were used to monitor thermal denaturation, acid base titration and mole ratio experiments. The resulting data were analyzed by multivariate data analysis methods. Surface plasmon resonance was also used to probe the kinetics and affinity of the DNA-drug interactions. Results We investigated the interaction between a G-quadruplex-forming sequence in the human c-kit proto-oncogene and the water soluble porphyrin TMPyP4. The role of cytosine and adenine residues at the loops of G-quadruplex was studied by substitution of these residues by thymidines. Conclusions Here, we show the existence of two binding modes between TMPyP4 and the considered G-quadruplex. The stronger binding mode (formation constant around 107) involves end-stacking, while the weaker binding mode (formation constant around 106) is probably due to external loop binding. Evidence for the release of TMPyP4 upon protonation of bases at the loops has been observed. General significance The results may be used for the design of porphyrin-based anti-cancer molecules with a higher affinity to G-quadruplex structures which may have anticancer properties. Graphical abstract Protonation pushes away TMPyP4 molecules from the loops in G-quadruplex structures. The interaction of TMPyP4 porphyrin with the G-quadruplex structure formed by a guanine-rich sequence in the promoter region of c-kit gene was studied. Up to three ligand molecules may be bound to the G-quadruplex structure. Protonation at the loops induces the release of one TMPyP4 molecule.Elsevier B.V.2019201920122019info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion10 p.application/pdfhttps://hdl.handle.net/2445/128186Articles publicats en revistes (Enginyeria Química i Química Analítica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1016/j.bbagen.2012.09.006Biochimica et Biophysica Acta-General Subjects, 2012, vol. 1820, num. 12, p. 1987-1996https://doi.org/10.1016/j.bbagen.2012.09.006(c) Elsevier B.V., 2012info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1281862026-05-29T05:05:01Z
dc.title.none.fl_str_mv Porphyrin binding mechanism is altered by protonation at the loops in G-quadruplex DNA formed near the transcriptional activation site of the human c-kit gene
title Porphyrin binding mechanism is altered by protonation at the loops in G-quadruplex DNA formed near the transcriptional activation site of the human c-kit gene
spellingShingle Porphyrin binding mechanism is altered by protonation at the loops in G-quadruplex DNA formed near the transcriptional activation site of the human c-kit gene
Manaye, Sintayehu
Porfirines
Telòmer
Expressió gènica
Oncogens
Porphyrins
Telomere
Gene expression
Oncogenes
title_short Porphyrin binding mechanism is altered by protonation at the loops in G-quadruplex DNA formed near the transcriptional activation site of the human c-kit gene
title_full Porphyrin binding mechanism is altered by protonation at the loops in G-quadruplex DNA formed near the transcriptional activation site of the human c-kit gene
title_fullStr Porphyrin binding mechanism is altered by protonation at the loops in G-quadruplex DNA formed near the transcriptional activation site of the human c-kit gene
title_full_unstemmed Porphyrin binding mechanism is altered by protonation at the loops in G-quadruplex DNA formed near the transcriptional activation site of the human c-kit gene
title_sort Porphyrin binding mechanism is altered by protonation at the loops in G-quadruplex DNA formed near the transcriptional activation site of the human c-kit gene
dc.creator.none.fl_str_mv Manaye, Sintayehu
Eritja i Casadellà, Ramon
Aviñó Andrés, Anna
Jaumot Soler, Joaquim
Gargallo Gómez, Raimundo
author Manaye, Sintayehu
author_facet Manaye, Sintayehu
Eritja i Casadellà, Ramon
Aviñó Andrés, Anna
Jaumot Soler, Joaquim
Gargallo Gómez, Raimundo
author_role author
author2 Eritja i Casadellà, Ramon
Aviñó Andrés, Anna
Jaumot Soler, Joaquim
Gargallo Gómez, Raimundo
author2_role author
author
author
author
dc.subject.none.fl_str_mv Porfirines
Telòmer
Expressió gènica
Oncogens
Porphyrins
Telomere
Gene expression
Oncogenes
topic Porfirines
Telòmer
Expressió gènica
Oncogens
Porphyrins
Telomere
Gene expression
Oncogenes
description Background G-quadruplex DNA structures are hypothesized to be involved in the regulation of gene expression and telomere homeostasis. The development of small molecules that modulate the stability of G-quadruplex structures has a potential therapeutic interest in cancer treatment and prevention of aging. Methods Molecular absorption and circular dichroism spectra were used to monitor thermal denaturation, acid base titration and mole ratio experiments. The resulting data were analyzed by multivariate data analysis methods. Surface plasmon resonance was also used to probe the kinetics and affinity of the DNA-drug interactions. Results We investigated the interaction between a G-quadruplex-forming sequence in the human c-kit proto-oncogene and the water soluble porphyrin TMPyP4. The role of cytosine and adenine residues at the loops of G-quadruplex was studied by substitution of these residues by thymidines. Conclusions Here, we show the existence of two binding modes between TMPyP4 and the considered G-quadruplex. The stronger binding mode (formation constant around 107) involves end-stacking, while the weaker binding mode (formation constant around 106) is probably due to external loop binding. Evidence for the release of TMPyP4 upon protonation of bases at the loops has been observed. General significance The results may be used for the design of porphyrin-based anti-cancer molecules with a higher affinity to G-quadruplex structures which may have anticancer properties. Graphical abstract Protonation pushes away TMPyP4 molecules from the loops in G-quadruplex structures. The interaction of TMPyP4 porphyrin with the G-quadruplex structure formed by a guanine-rich sequence in the promoter region of c-kit gene was studied. Up to three ligand molecules may be bound to the G-quadruplex structure. Protonation at the loops induces the release of one TMPyP4 molecule.
publishDate 2012
dc.date.none.fl_str_mv 2012
2019
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/128186
url https://hdl.handle.net/2445/128186
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1016/j.bbagen.2012.09.006
Biochimica et Biophysica Acta-General Subjects, 2012, vol. 1820, num. 12, p. 1987-1996
https://doi.org/10.1016/j.bbagen.2012.09.006
dc.rights.none.fl_str_mv (c) Elsevier B.V., 2012
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Elsevier B.V., 2012
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 10 p.
application/pdf
dc.publisher.none.fl_str_mv Elsevier B.V.
publisher.none.fl_str_mv Elsevier B.V.
dc.source.none.fl_str_mv Articles publicats en revistes (Enginyeria Química i Química Analítica)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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