title: CUX2 protein functions as an accessory factor in the repair of oxidative DNA damage.
abstract: CUX1 and CUX2 proteins are characterized by the presence of three highly similar regions called Cut repeats 1, 2, and 3. Although CUX1 is ubiquitously expressed, CUX2 plays an important role in the specification of neuronal cells and continues to be expressed in postmitotic neurons. Cut repeats from the CUX1 protein were recently shown to stimulate 8-oxoguanine DNA glycosylase 1 (OGG1), an enzyme that removes oxidized purines from DNA and introduces a single strand break through its apurinic/apyrimidinic lyase activity to initiate base excision repair. Here, we investigated whether CUX2 plays a similar role in the repair of oxidative DNA damage. Cux2 knockdown in embryonic cortical neurons increased levels of oxidative DNA damage. In vitro, Cut repeats from CUX2 increased the binding of OGG1 to 7,8-dihydro-8-oxoguanine-containing DNA and stimulated both the glycosylase and apurinic/apyrimidinic lyase activities of OGG1. Genetic inactivation in mouse embryo fibroblasts or CUX2 knockdown in HCC38 cells delayed DNA repair and increased DNA damage. Conversely, ectopic expression of Cut repeats from CUX2 accelerated DNA repair and reduced levels of oxidative DNA damage. These results demonstrate that CUX2 functions as an accessory factor that stimulates the repair of oxidative DNA damage. Neurons produce a high level of reactive oxygen species because of their dependence on aerobic oxidation of glucose as their source of energy. Our results suggest that the persistent expression of CUX2 in postmitotic neurons contributes to the maintenance of genome integrity through its stimulation of oxidative DNA damage repair.
authors.affiliation: From the Goodman Cancer Research Centre and.
authors.forename: Ranjana
authors.initials: R
authors.lastname: Pal
authors.affiliation: From the Goodman Cancer Research Centre and.
authors.forename: Zubaidah M
authors.initials: ZM
authors.lastname: Ramdzan
authors.affiliation: From the Goodman Cancer Research Centre and Departments of Biochemistry.
authors.forename: Simran
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Duquette
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto M5G 1L7, Canada, and.
authors.forename: Richard
authors.initials: R
authors.lastname: Marcotte
authors.affiliation: From the Goodman Cancer Research Centre and.
authors.forename: Lam
authors.initials: L
authors.lastname: Leduy
authors.affiliation: Departments of Biochemistry.
authors.forename: Sayeh
authors.initials: S
authors.lastname: Davoudi
authors.affiliation: Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lamarche-Vane
authors.affiliation: Department of Medical Neuroscience, Dalhousie University, Life Science Research Institute, Halifax B3H 4R2, Canada.
authors.forename: Angelo
authors.initials: A
authors.lastname: Iulianella
authors.affiliation: From the Goodman Cancer Research Centre and Departments of Biochemistry, Medicine, Oncology, and alain.nepveu@mcgill.ca.
authors.forename: Alain
authors.initials: A
authors.lastname: Nepveu
mesh_terms: D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C080632:CUX1 protein, human; C088424:Cux1 protein, rat; C101672:Cux2 protein, mouse; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D045647:DNA Glycosylases; C483741:OGG1 protein, rat; C485990:Ogg1 protein, mouse; C479058:oxoguanine glycosylase 1, human
keywords: 8-oxoguanine (8-oxoG); 8-oxoguanine glycosylase (OGG1); DNA damage; DNA repair; oxidative stress