title: A role for Myh1 in DNA repair after treatment with strand-breaking and crosslinking chemotherapeutic agents.
abstract: The highly conserved DNA glycosylase MutY is implicated in repair of oxidative DNA damage, in particular in removing adenines misincorporated opposite 7,8-dihydro-8-oxoguanine (8-oxo-G). The MutY homologues (MutYH) physically associate with proteins implicated in replication, DNA repair, and checkpoint signaling, specifically with the DNA damage sensor complex 9-1-1 proteins. Here, we ask whether MutYH could have a broader function in sensing and repairing different types of DNA damage induced by conventional chemotherapeutics. Thus, we examined if deletion of the Schizosaccharomyces pombe MutY homologue, Myh1, alone or in combination with deletion of either component of the 9-1-1 sensor complex, influences survival after exposure to different classes of DNA damaging chemotherapeutics that do not act primarily by causing 8-oxoG lesions. We show that Myh1 contributes to survival on genotoxic stresses induced by the oxidizing, DNA double strand break-inducing, bleomycins, or the DNA crosslinking platinum compounds, particularly in a rad1 mutant background. Exposure of cells to cisplatin leads to a moderate overall accumulation of Myh1 protein. Interestingly, we found that DNA damage induced by phleomycin results in increased chromatin association of Myh1. Further, we demonstrate that Myh1 relocalizes to the nucleus after exposure to hydrogen peroxide or chemotherapeutics, most prominently seen after phleomycin treatment. These observations indicate a wider role of Myh1 in DNA repair and DNA damage-induced checkpoint activation than previously thought.
authors.affiliation: Department of Chemistry and Molecular Biology, Lundberg Laboratory, University of Gothenburg, SE-405 30, Göteborg, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Jansson
authors.forename: John P
authors.initials: JP
authors.lastname: Alao
authors.forename: Kristina
authors.initials: K
authors.lastname: Viktorsson
authors.forename: Jonas
authors.initials: J
authors.lastname: Warringer
authors.forename: Rolf
authors.initials: R
authors.lastname: Lewensohn
authors.forename: Per
authors.initials: P
authors.lastname: Sunnerhagen
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000970:Antineoplastic Agents / Q000633:toxicity*; D015153:Blotting, Western; D002945:Cisplatin / Q000633:toxicity; D003432:Cross-Linking Reagents / Q000633:toxicity*; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D004271:DNA, Fungal / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D050296:Microbial Viability / Q000187:drug effects; D008856:Microscopy, Fluorescence; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D010692:Phleomycins / Q000633:toxicity; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004271:DNA, Fungal; D009944:Organoplatinum Compounds; D010692:Phleomycins; D029702:Schizosaccharomyces pombe Proteins; D000077150:Oxaliplatin; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D002945:Cisplatin