Activation of cellular signaling by 8-oxoguanine DNA glycosylase-1-initiated DNA base excision repair

Peter German, Peter Szaniszlo, Gyorgy Hajas, Zsolt Radak, Attila Bacsi, Tapas Hazra, Muralidhar L. Hegde, Xueqing Ba, Istvan Boldogh

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Accumulation of 8-oxo-7,8-dihydroguanine (8-oxoG) in the DNA results in genetic instability and mutagenesis, and is believed to contribute to carcinogenesis, aging processes and various aging-related diseases. 8-OxoG is removed from the DNA via DNA base excision repair (BER), initiated by 8-oxoguanine DNA glycosylase-1 (OGG1). Our recent studies have shown that OGG1 binds its repair product 8-oxoG base with high affinity at a site independent from its DNA lesion-recognizing catalytic site and the OGG1•8-oxoG complex physically interacts with canonical Ras family members. Furthermore, exogenously added 8-oxoG base enters the cells and activates Ras GTPases; however, a link has not yet been established between cell signaling and DNA BER, which is the endogenous source of the 8-oxoG base. In this study, we utilized KG-1 cells expressing a temperature-sensitive mutant OGG1, siRNA ablation of gene expression, and a variety of molecular biological assays to define a link between OGG1-BER and cellular signaling. The results show that due to activation of OGG1-BER, 8-oxoG base is released from the genome in sufficient quantities for activation of Ras GTPase and resulting in phosphorylation of the downstream Ras targets Raf1, MEK1,2 and ERK1,2. These results demonstrate a previously unrecognized mechanism for cellular responses to OGG1-initiated DNA BER.

Original languageEnglish (US)
Pages (from-to)856-863
Number of pages8
JournalDNA Repair
Volume12
Issue number10
DOIs
StatePublished - Oct 2013

Fingerprint

DNA Glycosylases
Cell signaling
DNA Repair
Repair
Chemical activation
DNA
ras Proteins
8-hydroxyguanine
Aging of materials
Mutagenesis
Phosphorylation
Ablation
Gene expression
Biological Assay
Small Interfering RNA
Assays
Catalytic Domain
Carcinogenesis
Genes

Keywords

  • Base excision repair
  • Cell signaling
  • Ogg1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Activation of cellular signaling by 8-oxoguanine DNA glycosylase-1-initiated DNA base excision repair. / German, Peter; Szaniszlo, Peter; Hajas, Gyorgy; Radak, Zsolt; Bacsi, Attila; Hazra, Tapas; Hegde, Muralidhar L.; Ba, Xueqing; Boldogh, Istvan.

In: DNA Repair, Vol. 12, No. 10, 10.2013, p. 856-863.

Research output: Contribution to journalArticle

German, Peter ; Szaniszlo, Peter ; Hajas, Gyorgy ; Radak, Zsolt ; Bacsi, Attila ; Hazra, Tapas ; Hegde, Muralidhar L. ; Ba, Xueqing ; Boldogh, Istvan. / Activation of cellular signaling by 8-oxoguanine DNA glycosylase-1-initiated DNA base excision repair. In: DNA Repair. 2013 ; Vol. 12, No. 10. pp. 856-863.
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