Huang Yaling, Leung Justin W C, Lowery Megan, Matsushita Nobuko, Wang Yucai, Shen Xi, Huong Do, Takata Minoru, Chen Junjie, Li Lei
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Rep. 2014 Jun 26;7(6):1849-57. doi: 10.1016/j.celrep.2014.04.029. Epub 2014 Jun 5.
The Fanconi anemia (FA) core complex provides the essential E3 ligase function for spatially defined FANCD2 ubiquitination and FA pathway activation. Of the seven FA gene products forming the core complex, FANCL possesses a RING domain with demonstrated E3 ligase activity. The other six components do not have clearly defined roles. Through epistasis analyses, we identify three functional modules in the FA core complex: a catalytic module consisting of FANCL, FANCB, and FAAP100 is absolutely required for the E3 ligase function, and the FANCA-FANCG-FAAP20 and the FANCC-FANCE-FANCF modules provide nonredundant and ancillary functions that help the catalytic module bind chromatin or sites of DNA damage. Disruption of the catalytic module causes complete loss of the core complex function, whereas loss of any ancillary module component does not. Our work reveals the roles of several FA gene products with previously undefined functions and a modularized assembly of the FA core complex.
范可尼贫血（FA）核心复合物为空间定义的FANCD2泛素化和FA途径激活提供必需的E3连接酶功能。在构成核心复合物的七种FA基因产物中，FANCL拥有一个具有已证实的E3连接酶活性的RING结构域。其他六种成分没有明确的作用。通过上位性分析，我们在FA核心复合物中鉴定出三个功能模块：由FANCL、FANCB和FAAP100组成的催化模块对于E3连接酶功能是绝对必需的，而FANCA-FANCG-FAAP20和FANCC-FANCE-FANCF模块提供非冗余的辅助功能，帮助催化模块结合染色质或DNA损伤位点。催化模块的破坏会导致核心复合物功能完全丧失，而任何辅助模块成分的缺失则不会。我们的工作揭示了几种以前功能未明的FA基因产物的作用以及FA核心复合物的模块化组装。
