期刊
ONCOTARGET
卷 8, 期 44, 页码 76443-76457出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.19470
关键词
fanconi anemia; FANCD2; FANCI; monoubiquitination; histone methylation
资金
- National Institutes of Health/National Heart, Lung and Blood Institute [R01HL101977]
- Rhode Island IDeA Network of Biomedical Research Excellence (RI-INBRE) grant from the National Institute of General Medical Sciences [P20GM103430]
- Rhode Island Experimental Program to Stimulate Competitive Research (RI-EPSCoR) grant from the National Science Foundation [1004057]
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR016457] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL101977] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P20GM103430] Funding Source: NIH RePORTER
Fanconi anemia (FA) is a rare disease characterized by congenital defects, bone marrow failure, and atypically early-onset cancers. The FA proteins function cooperatively to repair DNA interstrand crosslinks. A major step in the activation of the pathway is the monoubiquitination of the FANCD2 and FANCI proteins, and their recruitment to chromatin-associated nuclear foci. The regulation and function of FANCD2 and FANCI, however, is poorly understood. In addition, how chromatin state impacts pathway activation is also unknown. In this study, we have examined the influence of chromatin state on the activation of the FA pathway. We describe potent activation of FANCD2 and FANCI monoubiquitination and nuclear foci formation following treatment of cells with the histone methyltransferase inhibitor BRD4770. BRD4770-induced activation of the pathway does not occur via the direct induction of DNA damage or via the inhibition of the G9a histone methyltransferase, a mechanism previously proposed for this molecule. Instead, we show that BRD4770-inducible FANCD2 and FANCI monoubiquitination and nuclear foci formation may be a consequence of inhibition of the PRC2/EZH2 chromatin-modifying complex. In addition, we show that inhibition of the class I and II histone deacetylases leads to attenuated FANCD2 and FANCI monoubiquitination and nuclear foci formation. Our studies establish that chromatin state is a major determinant of the activation of the FA pathway and suggest an important role for the PRC2/EZH2 complex in the regulation of this critical tumor suppressor pathway.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据