Laboratory of Genetics, National Institute of Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Mol Cell. 2012 Jul 13;47(1):61-75. doi: 10.1016/j.molcel.2012.05.026. Epub 2012 Jun 14.
The Fanconi anemia (FA) protein network is necessary for repair of DNA interstrand crosslinks (ICLs), but its control mechanism remains unclear. Here we show that the network is regulated by a ubiquitin signaling cascade initiated by RNF8 and its partner, UBC13, and mediated by FAAP20, a component of the FA core complex. FAAP20 preferentially binds the ubiquitin product of RNF8-UBC13, and this ubiquitin-binding activity and RNF8-UBC13 are both required for recruitment of FAAP20 to ICLs. Both RNF8 and FAAP20 are required for recruitment of FA core complex and FANCD2 to ICLs, whereas RNF168 can modulate efficiency of the recruitment. RNF8 and FAAP20 are needed for efficient FANCD2 monoubiquitination, a key step of the FA network; RNF8 and the FA core complex work in the same pathway to promote cellular resistance to ICLs. Thus, the RNF8-FAAP20 ubiquitin cascade is critical for recruiting FA core complex to ICLs and for normal function of the FA network.
范可尼贫血（FA）蛋白网络对于修复 DNA 链间交联（ICLs）是必要的，但它的调控机制尚不清楚。在这里，我们表明该网络受 RNF8 和其伴侣 UBC13 起始的泛素信号级联的调控，并通过 FAAP20 介导，FAAP20 是 FA 核心复合物的一个组成部分。FAAP20 优先结合 RNF8-UBC13 的泛素产物，这种泛素结合活性和 RNF8-UBC13 都需要 FAAP20 募集到 ICL 上。RNF8 和 FAAP20 都需要募集 FA 核心复合物和 FANCD2 到 ICL 上，而 RNF168 可以调节募集的效率。RNF8 和 FAAP20 对于 FANCD2 的单泛素化（FA 网络的关键步骤）是必需的；RNF8 和 FA 核心复合物在同一途径中起作用，以促进细胞对 ICL 的抗性。因此，RNF8-FAAP20 泛素级联对于将 FA 核心复合物募集到 ICL 上以及 FA 网络的正常功能至关重要。
