n408069SE Academic Article uri icon

abstract

  • Maintenance of genomic integrity is an essential cellular function. We previously reported that the transcription factor and tumor suppressor CCAAT/enhancer binding protein (C/EBP, CEBPD; also known as "NFIL-6") promotes genomic stability. However, the molecular mechanism was not known. Here, we show that C/EBP 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 promotes monoubiquitination of the Fanconi anemia complementation group D2 protein (FANCD2), which is necessary for its function in replication-associated DNA repair. C/EBP 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 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.

published proceedings

  • Proc Natl Acad Sci U S A

author list (cited authors)

  • Wang, J., Sarkar, T. R., Zhou, M., Sharan, S., Ritt, D. A., Veenstra, T. D., ... Sterneck, E

publication date

  • January 1, 2010 11:11 AM