title: The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters.
abstract: Oxidative stress has been implicated in the pathogenesis of many human diseases including Fanconi anemia (FA), a genetic disorder associated with BM failure and cancer. Here we show that major antioxidant defense genes are down-regulated in FA patients, and that gene down-regulation is selectively associated with increased oxidative DNA damage in the promoters of the antioxidant defense genes. Assessment of promoter activity and DNA damage repair kinetics shows that increased initial damage, rather than a reduced repair rate, contributes to the augmented oxidative DNA damage. Mechanistically, FA proteins act in concert with the chromatin-remodeling factor BRG1 to protect the promoters of antioxidant defense genes from oxidative damage. Specifically, BRG1 binds to the promoters of the antioxidant defense genes at steady state. On challenge with oxidative stress, FA proteins are recruited to promoter DNA, which correlates with significant increase in the binding of BRG1 within promoter regions. In addition, oxidative stress-induced FANCD2 ubiquitination is required for the formation of a FA-BRG1-promoter complex. Taken together, these data identify a role for the FA pathway in cellular antioxidant defense.
authors.affiliation: Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.forename: Reena
authors.initials: R
authors.lastname: Rani
authors.forename: Jared
authors.initials: J
authors.lastname: Sipple
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schick
authors.forename: Kasiani C
authors.initials: KC
authors.lastname: Myers
authors.forename: Parinda
authors.initials: P
authors.lastname: Mehta
authors.forename: Paul R
authors.initials: PR
authors.lastname: Andreassen
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
authors.forename: Qishen
authors.initials: Q
authors.lastname: Pang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000975:Antioxidants; D001854:Bone Marrow Cells / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism; D004260:DNA Repair; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D015536:Down-Regulation; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051856:Fanconi Anemia Complementation Group Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D046912:Multiprotein Complexes; D009687:Nuclear Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D014157:Transcription Factors / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D000975:Antioxidants; D051856:Fanconi Anemia Complementation Group Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D014157:Transcription Factors; D000080242:8-Hydroxy-2'-Deoxyguanosine; D006861:Hydrogen Peroxide; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D003849:Deoxyguanosine