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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 ? (C/EBP?, CEBPD; also known as "NFIL-6?") promotes genomic stability. However, the molecular mechanism was not known. Here, we show that C/EBP? 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? promotes monoubiquitination of the Fanconi anemia complementation group D2 protein (FANCD2), which is necessary for its function in replication-associated DNA repair. C/EBP? 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? 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.

SUBMITTER: Wang J

PROVIDER: S-EPMC2941265 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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

Wang Jun J 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

Proceedings of the National Academy of Sciences of the United States of America 20100830 37

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 cro ...[more]

PMID: 20805509

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Project description:α-Synuclein is the main component of Lewy bodies, the intracellular protein aggregates representing the histological hallmark of Parkinson's disease. Elevated α-synuclein levels and mutations in SNCA gene are associated with increased risk for Parkinson's disease. Despite this, little is known about the molecular mechanisms regulating SNCA transcription. CCAAT/enhancer binding protein (C/EBP) β and δ are b-zip transcription factors that play distinct roles in neurons and glial cells. C/EBPβ overexpression increases SNCA expression in neuroblastoma cells and putative C/EBPβ and δ binding sites are present in the SNCA genomic region suggesting that these proteins could regulate SNCA transcription. Based on these premises, the goal of this study was to determine if C/EBPβ and δ regulate the expression of SNCA. We first observed that α-synuclein CNS expression was not affected by C/EBPβ deficiency but it was markedly increased in C/EBPδ-deficient mice. This prompted us to characterize further the role of C/EBPδ in SNCA transcription. C/EBPδ absence led to the in vivo increase of α-synuclein in all brain regions analyzed, both at mRNA and protein level, and in primary neuronal cultures. In agreement with this, CEBPD overexpression in neuroblastoma cells and in primary neuronal cultures markedly reduced SNCA expression. ChIP experiments demonstrated C/EBPδ binding to the SNCA genomic region of mice and humans and luciferase experiments showed decreased expression of a reporter gene attributable to C/EBPδ binding to the SNCA promoter. Finally, decreased CEBPD expression was observed in the substantia nigra and in iPSC-derived dopaminergic neurons from Parkinson patients resulting in a significant negative correlation between SNCA and CEBPD levels. This study points to C/EBPδ as an important repressor of SNCA transcription and suggests that reduced C/EBPδ neuronal levels could be a pathogenic factor in Parkinson's disease and other synucleinopathies and C/EBPδ activity a potential pharmacological target for these neurological disorders.

Dataset Information

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

Publications

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

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