Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4491-6. doi: 10.1073/pnas.1118720109. Epub 2012 Mar 6.
The Fanconi anemia (FA) pathway participates in interstrand cross-link (ICL) repair and the maintenance of genomic stability. The FA core complex consists of eight FA proteins and two Fanconi anemia-associated proteins (FAAP24 and FAAP100). The FA core complex has ubiquitin ligase activity responsible for monoubiquitination of the FANCI-FANCD2 (ID) complex, which in turn initiates a cascade of biochemical events that allow processing and removal of cross-linked DNA and thereby promotes cell survival following DNA damage. Here, we report the identification of a unique component of the FA core complex, namely, FAAP20, which contains a RAD18-like ubiquitin-binding zinc-finger domain. Our data suggest that FAAP20 promotes the functional integrity of the FA core complex via its direct interaction with the FA gene product, FANCA. Indeed, somatic knockout cells devoid of FAAP20 displayed the hallmarks of FA cells, including hypersensitivity to DNA cross-linking agents, chromosome aberrations, and reduced FANCD2 monoubiquitination. Taking these data together, our study indicates that FAAP20 is an important player involved in the FA pathway.
范可尼贫血（FA）途径参与链间交联（ICL）修复和基因组稳定性的维持。FA 核心复合物由 8 种 FA 蛋白和 2 种 FA 相关蛋白（FAAP24 和 FAAP100）组成。FA 核心复合物具有泛素连接酶活性，负责单泛素化 FANCI-FANCD2（ID）复合物，进而引发一系列生化事件，允许交联 DNA 的加工和去除，从而促进 DNA 损伤后的细胞存活。在这里，我们报告了 FA 核心复合物的一个独特成分的鉴定，即 FAAP20，它包含一个 RAD18 样泛素结合锌指结构域。我们的数据表明，FAAP20 通过其与 FA 基因产物 FANCA 的直接相互作用来促进 FA 核心复合物的功能完整性。事实上，缺乏 FAAP20 的体细胞敲除细胞表现出 FA 细胞的特征，包括对 DNA 交联剂、染色体畸变和 FANCD2 单泛素化的敏感性降低。综上所述，我们的研究表明 FAAP20 是 FA 途径中一个重要的参与者。
