title: Phosphorylation of human oxoguanine DNA glycosylase (alpha-OGG1) modulates its function.
abstract: Oxoguanine DNA glycosylase (OGG1) initiates the repair of 8-oxoguanine (8-oxoG), a major oxidative DNA base modification that has been directly implicated in cancer and aging. OGG1 functions in the base excision repair pathway, for which a molecular hand-off mechanism has been proposed. To date, only one functional and a few physical protein interactions have been reported for OGG1. Using the yeast two-hybrid system and a protein array membrane, we identified two novel protein interactions of OGG1, with two different protein kinases: Cdk4, a serine-threonine kinase, and c-Abl, a tyrosine kinase. We confirmed these interactions in vitro using recombinant proteins and in vivo by co-immunoprecipitation from whole cell extracts. OGG1 is phosphorylated in vitro by Cdk4, resulting in a 2.5-fold increase in the 8-oxoG/C incision activity of OGG1. C-Abl tyrosine phosphorylates OGG1 in vitro; however, this phosphorylation event does not affect OGG1 8-oxoG/C incision activity. These results provide the first evidence that a post-translational modification of OGG1 can affect its catalytic activity. The distinct functional outcomes from serine/threonine or tyrosine phosphorylation may indicate that activation of different signal transduction pathways modulate OGG1 activity in different ways.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH Baltimore, MD 21224, USA.
authors.forename: Jingping
authors.initials: J
authors.lastname: Hu
authors.forename: Syed Z
authors.initials: SZ
authors.lastname: Imam
authors.forename: Kazunari
authors.initials: K
authors.lastname: Hashiguchi
authors.forename: Nadja C
authors.initials: NC
authors.lastname: de Souza-Pinto
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D002460:Cell Line; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D045647:DNA Glycosylases / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; D016315:Proto-Oncogene Proteins c-abl; D011493:Protein Kinase C; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human