CCAAT/Enhancer Binding Protein Delta (C/EBPdelta, CEBPD)-Mediated Nuclear Import of FANCD2 by IPO4 Augments Cellular Response to DNA Damage
Proceedings of the National Academy of Sciences of the United States of America
PubMed Central® ID
Maintenance of genomic integrity is an essential cellular function. We previously reported that the transcription factor and tumor suppressor CCAAT/enhancer binding protein δ (C/EBPδ, CEBPD; also known as "NFIL-6β") promotes genomic stability. However, the molecular mechanism was not known. Here, we show that C/EBPδ 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/EBPδ promotes monoubiquitination of the Fanconi anemia complementation group D2 protein (FANCD2), which is necessary for its function in replication-associated DNA repair. C/EBPδ 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/EBPδ 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.
Active transport, cell nucleus, CCAAT-enhancer-binding protein-delta, Cell Line, DNA damage, Fanconi Anemia Complementation Group D2 protein, protein binding
Wang, Jun; Sarkar, Tapasree Roy; Zhou, Ming; Sharan, Shikha; Ritt, Daniel A.; Veenstra, Timothy D.; Morrison, Deborah K.; Huang, A-Mei; and Sterneck, Esta, "CCAAT/Enhancer Binding Protein Delta (C/EBPdelta, CEBPD)-Mediated Nuclear Import of FANCD2 by IPO4 Augments Cellular Response to DNA Damage" (2010). Pharmaceutical Sciences Faculty Publications. 271.