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