Pharmaceutical Sciences Faculty Publications

CCAAT/Enhancer Binding Protein Delta (C/EBPdelta, CEBPD)-Mediated Nuclear Import of FANCD2 by IPO4 Augments Cellular Response to DNA Damage

Document Type

Article

Publication Date

9-14-2010

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

ISSN

1091-6490

Volume

107

Issue

37

First Page

16131

Last Page

16136

DOI

10.1073/pnas.1002603107

PubMed ID

20805509

PubMed Central® ID

PMC2941265

Abstract

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.

Keywords

Active transport, cell nucleus, CCAAT-enhancer-binding protein-delta, Cell Line, DNA damage, Fanconi Anemia Complementation Group D2 protein, protein binding

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