The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters

Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA.
Blood (Impact Factor: 10.45). 03/2012; 119(18):4142-51. DOI: 10.1182/blood-2011-09-381970
Source: PubMed


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.

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Available from: Wei Du, Dec 04, 2015
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    • "The deficiency of Brg1 results in the dissolution of discrete heterochromatin domains, aberrant mitotic progression, and genomic instability, which eventually induces cell death or cell apoptosis [12]. A recent study showed that Brg1 can bind to the promoters of antioxidant defense genes and protect cells from oxidative damage [13], which means that Brg1 can exert antioxidative effect. Furthermore, increasing evidence shows that Brg1 can regulate gene expression during cardiac growth, differentiation, and hypertrophy [14] [15] [16]. "
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