title: Regulation of oxidative DNA damage repair: the adenine:8-oxo-guanine problem.
abstract: Reactive oxygen species (ROS) constantly attack DNA. One of the best-characterized oxidative DNA lesions is 7,8-dihydro-8-oxoguanine (8-oxo-G). Many human diseases, such as cancer and neurodegenerative disorders, have been correlated with oxidative DNA damage. In the last few years, DNA polymerase (Pol) λ, one of the 15 cellular Pols, has been identified to play an important role in performing accurate translesion synthesis over 8-oxo-G. This is eminently important, since normally faithful replicative Pols α, δ and ε, with their tight active center, often wrongly incorporate adenine (A) opposite the 8-oxo-G lesion. A:8- oxo-G mispairs are accurately repaired by the pathway identified in our laboratory involving MutY DNA glycosylase homolog (MutYH) and Pol λ. Until now, very little was known about the spatial and temporal regulation of Pol λ and MutYH in active repair complexes. We now showed in our latest publication that the E3 ligase Mule can ubiquitinate and degrade Pol λ, and that the control of Pol λ levels by Mule has functional consequences for the ability of mammalian cells to deal with 8-oxo-G lesions. In contrast, phosphorylation of Pol λ by Cdk2/cyclinA counteracts this degradation by recruiting it to MutYH on chromatin to form active 8-oxo-G repair complexes.
authors.affiliation: Institute for Veterinary Biochemistry and Molecular Biology; University of Zürich-Irchel; Zürich, Switzerland.
authors.forename: Enni
authors.initials: E
authors.lastname: Markkanen
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hübscher
authors.forename: Barbara
authors.initials: B
authors.lastname: van Loon
mesh_terms: D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D000074002:DNA Polymerase gamma; D004260:DNA Repair; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D015894:Genome, Human; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress; D010766:Phosphorylation; D021381:Protein Transport; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013379:Substrate Specificity; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C453560:7,8-dihydro-8-oxoguanine; D002843:Chromatin; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D006147:Guanine; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase