Host: The Japan Radiation Research Society
Fanconi anemia (FA) is a rare hereditary disorder characterized by progressive bone marrow failure, compromised genome stability, and increased incidence of cancer. FA is caused by genetic defects in altogether 13 genes, which include components of the FA core complex (FancA/B/C/E/F/G/L/M), a key factor FancD2, breast cancer protein BRCA2/FancD1, BRIP1/FancJ helicase, and just recently identified FANCI. In the DNA damage response, FancD2 is targeted to chromatin and forms nuclear foci following its monoubiquitination (mono-Ub), a process catalyzed by the FA core complex. This mono-Ub is critical for regulating nuclear dynamics of FancD2 as well as DNA repair through homologous recombination. We reported the core complex also has function in chromatin targeting of monoubiquitinated FANCD2 and DNA repair. However, the newest member of the FA pathway, FANCI, is found to be monoubiquitinated, and to interact with FANCD2 (called ID complex), raising a possibility that these additional functions are actually mediated by monoubiquitinated FANCI. We investigated roles of FANCI phosphorylation and mono-Ub using mutant proteins and ubiquitin fusions expressed in DT40 knockout cell lines. Our results indicate that FANCI is an essential co-factor for FANCD2 regulation and its function.
