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

被引:51
|
作者
Du, Wei [1 ]
Rani, Reena [1 ]
Sipple, Jared [1 ]
Schick, Jonathan [1 ]
Myers, Kasiani C. [2 ,3 ]
Mehta, Parinda [2 ,3 ]
Andreassen, Paul R. [1 ,3 ]
Davies, Stella M. [2 ,3 ]
Pang, Qishen [1 ,3 ]
机构
[1] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA
[2] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplant & Immune Deficiency Re, Cincinnati, OH 45229 USA
[3] Univ Cincinnati Coll Med, Dept Pediat, Cincinnati, OH USA
基金
美国国家卫生研究院;
关键词
FANCONI-ANEMIA PROTEIN; TRANSCRIPTION FACTOR-BINDING; DNA-DAMAGE; HISTONE ACETYLATION; SWI/SNF COMPLEX; EXCISION-REPAIR; CHROMATIN; BRG1; FANCD2; CARCINOGENESIS;
D O I
10.1182/blood-2011-09-381970
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. (Blood. 2012;119(18):4142-4151)
引用
收藏
页码:4142 / 4151
页数:10
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