TY - JOUR
T1 - CCAAT/enhancer binding protein delta (C/EBPδ, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage
AU - Wang, Jun
AU - Sarkar, Tapasree Roy
AU - Zhou, Ming
AU - Sharan, Shikha
AU - Ritt, Daniel A.
AU - Veenstra, Timothy D.
AU - Morrison, Deborah K.
AU - Huang, A. Mei
AU - Sterneck, Esta
PY - 2010/9/14
Y1 - 2010/9/14
N2 - 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.
AB - 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.
KW - DNA repair
KW - Fanconi anemia
KW - Importin 4
KW - Mitomycin C
KW - Protein adaptor
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U2 - 10.1073/pnas.1002603107
DO - 10.1073/pnas.1002603107
M3 - Article
C2 - 20805509
AN - SCOPUS:77958021483
SN - 0027-8424
VL - 107
SP - 16131
EP - 16136
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 37
ER -