title: Activation of ras signaling pathway by 8-oxoguanine DNA glycosylase bound to its excision product, 8-oxoguanine.
abstract: 8-Oxo-7,8-dihydroguanine (8-oxoG), arguably the most abundant base lesion induced in mammalian genomes by reactive oxygen species, is repaired via the base excision repair pathway that is initiated with the excision of 8-oxoG by OGG1. Here we show that OGG1 binds the 8-oxoG base with high affinity and that the complex then interacts with canonical Ras family GTPases to catalyze replacement of GDP with GTP, thus serving as a guanine nuclear exchange factor. OGG1-mediated activation of Ras leads to phosphorylation of the mitogen-activated kinases MEK1,2/ERK1,2 and increasing downstream gene expression. These studies document for the first time that in addition to its role in repairing oxidized purines, OGG1 has an independent guanine nuclear exchange factor activity when bound to 8-oxoG.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch,Galveston, Texas 77555, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Hajas
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Aguilera-Aguirre
authors.forename: Muralidhar L
authors.initials: ML
authors.lastname: Hegde
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Radak
authors.forename: Attila
authors.initials: A
authors.lastname: Bacsi
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Sur
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Hazra
authors.forename: Sankar
authors.initials: S
authors.lastname: Mitra
mesh_terms: D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015894:Genome, Human / Q000502:physiology; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000235:genetics / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D006153:Guanosine Diphosphate; C024829:8-hydroxyguanine; D006147:Guanine; D006160:Guanosine Triphosphate; D020929:Mitogen-Activated Protein Kinase Kinases; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D018631:ras Proteins