Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
Genes Dev. 2011 Sep 1;25(17):1847-58. doi: 10.1101/gad.17020911.
The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that the regulated targeting of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinates homologous recombination and translesion DNA synthesis.
USP1/UAF1 复合物使范可尼贫血蛋白 FANCD2 去泛素化，从而促进同源重组和 DNA 交联修复。但是 USP1/UAF1 如何靶向 FANCD2/FANCI 异二聚体仍然未知。在这里，我们表明 UAF1 在其 C 末端含有串联重复的 SUMO 样结构域（SLD1 和 SLD2）。SLD2 直接与 FANCI 上的 SUMO 样结构域相互作用基序（SIM）结合。UAF1 的 SLD2 序列缺失或 FANCI 上 SIM 的突变会破坏 UAF1/FANCI 结合并抑制 FANCD2 去泛素化和 DNA 修复。USP1/UAF1 复合物还可使 PCNA-Ub 去泛素化，去泛素化需要 PCNA 结合蛋白 hELG1。UAF1 的 SLD2 序列与 hELG1 上的 SIM 结合，从而将 USP1/UAF1 复合物靶向其 PCNA-Ub 底物。我们提出，通过 SLD-SIM 相互作用，USP1/UAF1 复合物对其 DNA 修复底物 FANCD2-Ub 和 PCNA-Ub 的靶向调控，协调同源重组和跨损伤 DNA 合成。
