title: CCAAT/enhancer binding protein delta (C/EBPdelta, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage.
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.
authors.affiliation: Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Tapasree Roy
authors.initials: TR
authors.lastname: Sarkar
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Shikha
authors.initials: S
authors.lastname: Sharan
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Ritt
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Morrison
authors.forename: A-Mei
authors.initials: AM
authors.lastname: Huang
authors.forename: Esta
authors.initials: E
authors.lastname: Sterneck
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D004249:DNA Damage; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D006801:Humans; D028884:Karyopherins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D054875:Ubiquitination
chemical_list: C497252:CEBPD protein, human; C497253:Cebpd protein, mouse; C499905:FANCD2 protein, human; C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; C545055:IPO4 protein, human; D028884:Karyopherins; D026901:Membrane Transport Proteins; C553102:importin 4, mouse; D051743:CCAAT-Enhancer-Binding Protein-delta
references.citation: Annu Rev Genet. 2009;43:223-49
references.pmid: 19686080
references.citation: Oncogene. 2007 Mar 1;26(10):1507-16
references.pmid: 16936776
references.citation: Curr Opin Hematol. 2003 Jan;10(1):68-76
references.pmid: 12483114
references.citation: Mol Cell Biol. 2008 Jul;28(13):4331-41
references.pmid: 17682055
references.citation: Blood. 2007 May 1;109(9):3895-905
references.pmid: 17234736
references.citation: Cytometry. 1982 Mar;2(5):291-7
references.pmid: 6804195
references.citation: Breast Cancer Res Treat. 2006 Jan;95(2):161-70
references.pmid: 16322893
references.citation: EMBO J. 2002 Feb 1;21(3):377-86
references.pmid: 11823430
references.citation: Leukemia. 2010 Apr;24(4):679-86
references.pmid: 20130602
references.citation: Exp Parasitol. 2007 May;116(1):25-34
references.pmid: 17189633
references.citation: Mol Genet Metab. 2001 Dec;74(4):403-12
references.pmid: 11749045
references.citation: Gene Expr. 1997;6(6):371-85
references.pmid: 9495318
references.citation: Nat Rev Cancer. 2008 Dec;8(12):957-67
references.pmid: 19005492
references.citation: Nat Rev Cancer. 2003 Jan;3(1):23-34
references.pmid: 12509764
references.citation: Cancer Res. 2007 Jul 15;67(14):6725-36
references.pmid: 17638883
references.citation: Science. 2009 Dec 18;326(5960):1698-701
references.pmid: 19965384
references.citation: Biochem J. 2002 Aug 1;365(Pt 3):561-75
references.pmid: 12006103
references.citation: Mol Cancer Res. 2003 Mar;1(5):362-75
references.pmid: 12651909
references.citation: Oncogene. 2004 Feb 26;23(8):1549-57
references.pmid: 14716301
references.citation: Cell. 2005 Dec 29;123(7):1191-8
references.pmid: 16377561
references.citation: Cell Res. 2009 May;19(5):651-64
references.pmid: 19399029
references.citation: Mol Cell Biol. 1999 Aug;19(8):5441-52
references.pmid: 10409734
references.citation: DNA Repair (Amst). 2009 Sep 2;8(9):1055-67
references.pmid: 19497792
references.citation: Semin Cancer Biol. 2003 Feb;13(1):77-82
references.pmid: 12507559
references.citation: J Neurooncol. 2010 Apr;97(2):233-40
references.pmid: 19806320
references.citation: J Biol Chem. 2000 Aug 25;275(34):26582-90
references.pmid: 10856306
references.citation: J Biol Chem. 1996 Feb 16;271(7):3891-6
references.pmid: 8632009
references.citation: Biochem Biophys Res Commun. 2009 Dec 11;390(2):235-40
references.pmid: 19788888
references.citation: J Biol Chem. 2005 Dec 9;280(49):40901-8
references.pmid: 16207705
references.citation: Cancer Res. 2001 Aug 1;61(15):5697-702
references.pmid: 11479200
references.citation: J Biol Chem. 2003 Apr 25;278(17):15178-84
references.pmid: 12578822
references.citation: Traffic. 2009 Sep;10(9):1188-98
references.pmid: 19548983
references.citation: Carcinogenesis. 2006 Sep;27(9):1930-7
references.pmid: 16679306
references.citation: Biochem Pharmacol. 2010 Aug 1;80(3):325-34
references.pmid: 20385105
references.citation: Mutat Res. 2009 Jul 31;668(1-2):54-72
references.pmid: 19622404
references.citation: Mutagenesis. 2002 Nov;17(6):529-38
references.pmid: 12435850
references.citation: Hematol Oncol Clin North Am. 2009 Apr;23(2):193-214
references.pmid: 19327579
references.citation: Proc Natl Acad Sci U S A. 2010 May 18;107(20):9210-5
references.pmid: 20439707
references.citation: Am J Pathol. 2010 Jun;176(6):2935-47
references.pmid: 20363922
references.citation: J Biol Chem. 2008 Nov 7;283(45):30919-32
references.pmid: 18753137
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10908-13
references.pmid: 9724803