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Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites

Apurinic/apyrimidinic (AP) sites are constantly formed in cellular DNA due to instability of the glycosidic bond, particularly at purines and various oxidized, alkylated, or otherwise damaged nucleobases. AP sites are also generated by DNA glycosylases that initiate DNA base excision repair. These l...

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Autores principales: Minko, Irina G., Jacobs, Aaron C., de Leon, Arnie R., Gruppi, Francesca, Donley, Nathan, Harris, Thomas M., Rizzo, Carmelo J., McCullough, Amanda K., Lloyd, R. Stephen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929455/
https://www.ncbi.nlm.nih.gov/pubmed/27363485
http://dx.doi.org/10.1038/srep28894
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author Minko, Irina G.
Jacobs, Aaron C.
de Leon, Arnie R.
Gruppi, Francesca
Donley, Nathan
Harris, Thomas M.
Rizzo, Carmelo J.
McCullough, Amanda K.
Lloyd, R. Stephen
author_facet Minko, Irina G.
Jacobs, Aaron C.
de Leon, Arnie R.
Gruppi, Francesca
Donley, Nathan
Harris, Thomas M.
Rizzo, Carmelo J.
McCullough, Amanda K.
Lloyd, R. Stephen
author_sort Minko, Irina G.
collection PubMed
description Apurinic/apyrimidinic (AP) sites are constantly formed in cellular DNA due to instability of the glycosidic bond, particularly at purines and various oxidized, alkylated, or otherwise damaged nucleobases. AP sites are also generated by DNA glycosylases that initiate DNA base excision repair. These lesions represent a significant block to DNA replication and are extremely mutagenic. Some DNA glycosylases possess AP lyase activities that nick the DNA strand at the deoxyribose moiety via a β- or β,δ-elimination reaction. Various amines can incise AP sites via a similar mechanism, but this non-enzymatic cleavage typically requires high reagent concentrations. Herein, we describe a new class of small molecules that function at low micromolar concentrations as both β- and β,δ-elimination catalysts at AP sites. Structure-activity relationships have established several characteristics that appear to be necessary for the formation of an iminium ion intermediate that self-catalyzes the elimination at the deoxyribose ring.
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spelling pubmed-49294552016-07-06 Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites Minko, Irina G. Jacobs, Aaron C. de Leon, Arnie R. Gruppi, Francesca Donley, Nathan Harris, Thomas M. Rizzo, Carmelo J. McCullough, Amanda K. Lloyd, R. Stephen Sci Rep Article Apurinic/apyrimidinic (AP) sites are constantly formed in cellular DNA due to instability of the glycosidic bond, particularly at purines and various oxidized, alkylated, or otherwise damaged nucleobases. AP sites are also generated by DNA glycosylases that initiate DNA base excision repair. These lesions represent a significant block to DNA replication and are extremely mutagenic. Some DNA glycosylases possess AP lyase activities that nick the DNA strand at the deoxyribose moiety via a β- or β,δ-elimination reaction. Various amines can incise AP sites via a similar mechanism, but this non-enzymatic cleavage typically requires high reagent concentrations. Herein, we describe a new class of small molecules that function at low micromolar concentrations as both β- and β,δ-elimination catalysts at AP sites. Structure-activity relationships have established several characteristics that appear to be necessary for the formation of an iminium ion intermediate that self-catalyzes the elimination at the deoxyribose ring. Nature Publishing Group 2016-07-01 /pmc/articles/PMC4929455/ /pubmed/27363485 http://dx.doi.org/10.1038/srep28894 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Minko, Irina G.
Jacobs, Aaron C.
de Leon, Arnie R.
Gruppi, Francesca
Donley, Nathan
Harris, Thomas M.
Rizzo, Carmelo J.
McCullough, Amanda K.
Lloyd, R. Stephen
Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites
title Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites
title_full Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites
title_fullStr Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites
title_full_unstemmed Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites
title_short Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites
title_sort catalysts of dna strand cleavage at apurinic/apyrimidinic sites
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929455/
https://www.ncbi.nlm.nih.gov/pubmed/27363485
http://dx.doi.org/10.1038/srep28894
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