CCAAT/enhancer binding protein delta (C/EBPδ, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage

Maintenance of genomic integrity is an essential cellular function. We previously reported that the transcription factor and tumor suppressor CCAAT/enhancer binding protein delta (C/EBP delta, CEBPD; also known as NFIL-6 beta) promotes genomic stability. However, the molecular mechanism was not known. Here, we show that C/EBPd is a DNA damage-induced gene, which supports survival of mouse bone marrow cells, mouse embryo fibroblasts (MEF), human fibroblasts, and breast tumor cells in response to the DNA cross-linking agent mitomycin C (MMC). Using gene knockout, protein depletion, and overexpression studies, we found that C/EBP delta promotes monoubiquitination of the Fanconi anemia complementation group D2 protein (FANCD2), which is necessary for its function in replication-associated DNA repair. C/EBPd interacts with FANCD2 and importin 4 (IPO4, also known as Imp4 and RanBP4) via separate domains, mediating FANCD2-IPO4 association and augmenting nuclear import of FANCD2, a prerequisite for its monoubiquitination. This study identifies a transcription-independent activity of C/EBP delta in the DNA damage response that may in part underlie its tumor suppressor function. Furthermore, we report a function of IPO4 and nuclear import in the Fanconi anemia pathway of DNA repair.