Repair of DNA containing Fapy·dG and its β-C-nucleoside analogue by formamidopyrimidine DNA glycosylase and MutY

Carissa J. Wiederholt, Michael O. Delaney, Mary Ann Pope, Sheila S. David, Marc M. Greenberg

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Fapy·dG is produced in DNA as a result of oxidative stress. Under some conditions Fapy·dG is formed in greater yields than 8-oxodG from a common chemical precursor. Recently, Fapy·dG and its C-nucleoside analogue were incorporated in chemically synthesized oligonucleotides at defined sites. Like 8-oxodG, Fapy·dG instructs DNA polymerase to misincorporate dA opposite it in vitro. The interactions of DNA containing Fapy·dG or the nonhydrolyzable analogue with Fpg and MutY are described. Fpg excises Fapy·dG (KM = 2.0 nM, kcat = 0.14 min-1) opposite dC ∼17-fold more efficiently than when mispaired with dA, which is misinserted by DNA polymerase in vitro. Fpg also prefers to bind duplexes containing Fapy·dG·dC or β-C-Fapy·dG·dC compared to those in which the lesion is opposite dA. MutY incises dA when it is opposite Fapy·dG and strongly binds duplexes containing the lesion or β-C-Fapy· dG. Incision from Fapy·dG·dA is faster than from dG·dA mispairs but slower than from DNA containing 8-oxodG opposite dA. These data demonstrate that Fapy·dG closely resembles the interactions of 8-oxodG with two members of the GO repair pathway in vitro. The similar effects of Fapy·dG and 8-oxodG on DNA polymerase and repair enzymes in vitro raise the question as to whether Fapy·dG elicits similar effects in vivo.

Original languageEnglish (US)
Pages (from-to)9755-9760
Number of pages6
JournalBiochemistry
Volume42
Issue number32
DOIs
StatePublished - Aug 19 2003
Externally publishedYes

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DNA-Formamidopyrimidine Glycosylase
Nucleosides
DNA Repair
Repair
DNA-Directed DNA Polymerase
DNA
DNA Repair Enzymes
Oxidative stress
Oligonucleotides
Oxidative Stress
8-oxo-7-hydrodeoxyguanosine
In Vitro Techniques
Enzymes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Wiederholt, C. J., Delaney, M. O., Pope, M. A., David, S. S., & Greenberg, M. M. (2003). Repair of DNA containing Fapy·dG and its β-C-nucleoside analogue by formamidopyrimidine DNA glycosylase and MutY. Biochemistry, 42(32), 9755-9760. https://doi.org/10.1021/bi034844h

Repair of DNA containing Fapy·dG and its β-C-nucleoside analogue by formamidopyrimidine DNA glycosylase and MutY. / Wiederholt, Carissa J.; Delaney, Michael O.; Pope, Mary Ann; David, Sheila S.; Greenberg, Marc M.

In: Biochemistry, Vol. 42, No. 32, 19.08.2003, p. 9755-9760.

Research output: Contribution to journalArticle

Wiederholt, CJ, Delaney, MO, Pope, MA, David, SS & Greenberg, MM 2003, 'Repair of DNA containing Fapy·dG and its β-C-nucleoside analogue by formamidopyrimidine DNA glycosylase and MutY', Biochemistry, vol. 42, no. 32, pp. 9755-9760. https://doi.org/10.1021/bi034844h
Wiederholt, Carissa J. ; Delaney, Michael O. ; Pope, Mary Ann ; David, Sheila S. ; Greenberg, Marc M. / Repair of DNA containing Fapy·dG and its β-C-nucleoside analogue by formamidopyrimidine DNA glycosylase and MutY. In: Biochemistry. 2003 ; Vol. 42, No. 32. pp. 9755-9760.
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AB - Fapy·dG is produced in DNA as a result of oxidative stress. Under some conditions Fapy·dG is formed in greater yields than 8-oxodG from a common chemical precursor. Recently, Fapy·dG and its C-nucleoside analogue were incorporated in chemically synthesized oligonucleotides at defined sites. Like 8-oxodG, Fapy·dG instructs DNA polymerase to misincorporate dA opposite it in vitro. The interactions of DNA containing Fapy·dG or the nonhydrolyzable analogue with Fpg and MutY are described. Fpg excises Fapy·dG (KM = 2.0 nM, kcat = 0.14 min-1) opposite dC ∼17-fold more efficiently than when mispaired with dA, which is misinserted by DNA polymerase in vitro. Fpg also prefers to bind duplexes containing Fapy·dG·dC or β-C-Fapy·dG·dC compared to those in which the lesion is opposite dA. MutY incises dA when it is opposite Fapy·dG and strongly binds duplexes containing the lesion or β-C-Fapy· dG. Incision from Fapy·dG·dA is faster than from dG·dA mispairs but slower than from DNA containing 8-oxodG opposite dA. These data demonstrate that Fapy·dG closely resembles the interactions of 8-oxodG with two members of the GO repair pathway in vitro. The similar effects of Fapy·dG and 8-oxodG on DNA polymerase and repair enzymes in vitro raise the question as to whether Fapy·dG elicits similar effects in vivo.

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