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

  1. Author:
    Wang, J.
    Sarkar, T. R.
    Zhou, M.
    Sharan, S.
    Ritt, D. A.
    Veenstra, T. D.
    Morrison, D. K.
    Huang, A. M.
    Sterneck, E.

  2. Author Address

    [Wang, Jun; Sarkar, Tapasree Roy; Sharan, Shikha; Ritt, Daniel A.; Morrison, Deborah K.; Huang, A-Mei; Sterneck, Esta] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, Frederick, MD 21702 USA. [Zhou, Ming; Veenstra, Timothy D.] SAIC Frederick, Lab Prote & Analyt Technol, Adv Technol Program, Frederick, MD 21702 USA.;Sterneck, E, NCI, Lab Cell & Dev Signaling, Ctr Canc Res, Frederick, MD 21702 USA.;sternecg@mail.nih.gov
    1. Year: 2010
    2. Date: Sep
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 107
    2. 37
    3. Pages: 16131-16136
  4. Type of Article: Article
  5. ISSN: 0027-8424
  1. Abstract:

    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.

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External Sources

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  2. DOI: 10.1073/pnas.1002603107
  3. View record in Web of Science®
  4. WOS: 000281799000030

Library Notes

  1. Fiscal Year: FY2009-2010
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