The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters
| Autor: | Stella M. Davies, Wei Du, Paul R. Andreassen, Jared Sipple, Jonathan Schick, Reena Rani, Kasiani C. Myers, Qishen Pang, Parinda A. Mehta |
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| Rok vydání: | 2012 |
| Předmět: |
DNA Repair
Hematopoiesis and Stem Cells DNA repair DNA damage Immunology Down-Regulation Bone Marrow Cells Oxidative phosphorylation Biology medicine.disease_cause Biochemistry Antioxidants medicine Humans Promoter Regions Genetic Gene Transcription factor Cells Cultured Regulation of gene expression DNA Helicases Ubiquitination Deoxyguanosine Nuclear Proteins Promoter Hydrogen Peroxide Cell Biology Hematology Fanconi Anemia Complementation Group Proteins Oxidative Stress Fanconi Anemia Gene Expression Regulation 8-Hydroxy-2'-Deoxyguanosine Multiprotein Complexes Oxidation-Reduction Protein Processing Post-Translational Oxidative stress DNA Damage Protein Binding Transcription Factors |
| Zdroj: | Blood. 119:4142-4151 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2011-09-381970 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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