Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites

Irina G. Minko, Aaron C. Jacobs, Arnie R. De Leon, Francesca Gruppi, Nathan Donley, Thomas M. Harris, Carmelo J. Rizzo, Amanda K. McCullough, R. Stephen Lloyd

Research output: Research - peer-reviewArticle

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Abstract

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,Î-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,Î-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.

LanguageEnglish (US)
Article number28894
JournalScientific Reports
Volume6
DOIs
StatePublished - Jul 1 2016

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Catalysts
DNA
DNA Glycosylases
Deoxyribose
Purines
Lyases
Amines
Repair
Ions
Molecules

ASJC Scopus subject areas

  • General

Cite this

Minko, I. G., Jacobs, A. C., De Leon, A. R., Gruppi, F., Donley, N., Harris, T. M., ... Lloyd, R. S. (2016). Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites. Scientific Reports, 6, [28894]. DOI: 10.1038/srep28894

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.

In: Scientific Reports, Vol. 6, 28894, 01.07.2016.

Research output: Research - peer-reviewArticle

Minko, IG, Jacobs, AC, De Leon, AR, Gruppi, F, Donley, N, Harris, TM, Rizzo, CJ, McCullough, AK & Lloyd, RS 2016, 'Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites' Scientific Reports, vol 6, 28894. DOI: 10.1038/srep28894
Minko IG, Jacobs AC, De Leon AR, Gruppi F, Donley N, Harris TM et al. Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites. Scientific Reports. 2016 Jul 1;6. 28894. Available from, DOI: 10.1038/srep28894
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. In: Scientific Reports. 2016 ; Vol. 6.
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