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

Wang, Jun; Sarkar, Tapasree Roy; Zhou, Ming; Sharan, Shikha; Ritt, Daniel A.; Veenstra, Timothy D.; Morrison, Deborah K.; Huang, A-Mei; Sterneck, Esta

doi:10.1073/pnas.1002603107

Cited by 39 publications

(35 citation statements)

References 38 publications

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“…From a wider perspective, our findings of the 53BP1-NUP153/importin-b pathway as an important aspect of the DDR network add to an emerging evidence of subcellular trafficking as an integral part of genome surveillance. Such evidence encompasses ATM-regulated nuclear export 29 and import, 30 as well as the import of essential genome caretakers, such as the FANCD2, RAD51 or BRCA1 repair proteins, [31][32][33] ribonucleotide reductases, 34 DNA damageregulated transcription factors, 35 the ATM-activator protein Aven 36 or p53 tumor suppressor. 37 Although our overall understanding of the role(s) for mammalian NUPs and NPCs in genome maintenance is still in its infancy, significant advances in this research area have already been made based on experiments with yeast models.…”

Section: Discussionmentioning

confidence: 99%

Nucleoporin NUP153 guards genome integrity by promoting nuclear import of 53BP1

et al. 2011

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53BP1 is a mediator of DNA damage response (DDR) and a tumor suppressor whose accumulation on damaged chromatin promotes DNA repair and enhances DDR signaling. Using foci formation of 53BP1 as a readout in two human cell lines, we performed an siRNA-based functional high-content microscopy screen for modulators of cellular response to ionizing radiation (IR). Here, we provide the complete results of this screen as an information resource, and validate and functionally characterize one of the identified 'hits': a nuclear pore component NUP153 as a novel factor specifically required for 53BP1 nuclear import. Using a range of cell and molecular biology approaches including live-cell imaging, we show that knockdown of NUP153 prevents 53BP1, but not several other DDR factors, from entering the nuclei in the newly forming daughter cells. This translates into decreased IR-induced 53BP1 focus formation, delayed DNA repair and impaired cell survival after IR. In addition, NUP153 depletion exacerbates DNA damage caused by replication stress. Finally, we show that the C-terminal part of NUP153 is required for effective 53BP1 nuclear import, and that 53BP1 is imported to the nucleus through the NUP153-importin-b interplay. Our data define the structure-function relationships within this emerging 53BP1-NUP153/importin-b pathway and implicate this mechanism in the maintenance of genome integrity. Cell Death and Differentiation (2012) 19, 798-807; doi:10.1038/cdd.2011; published online 11 November 2011The cellular DNA damage response (DDR) machinery serves as a biological barrier against accumulation of genetic changes associated with aging, and guards against neurodegenerative and immunodeficiency disorders and cancer. 1 The proximal DDR kinases ATM, ATR and DNA-PK have a central role in response to various DNA lesions including DNA double strand breaks (DSBs), in part by phosphorylating histone H2AX (gH2AX) and its sensor MDC1, which in turn coordinates recruitment of signaling and repair factors to DNA damage foci. 1-4 These foci include 53BP1 5,6 whose retention at the DSB-flanking chromatin requires histone ubiquitylation by E3-ubiquitin ligases RNF8, RNF168 and HERC2, SUMOylation by the PIAS4/UBC9 complex, and histone methylation by MMSET and SET8 methyltransferases. [1][2][3]7 Apart from the role of 53BP1 in telomere maintenance, cell cycle checkpoints and DNA repair by non-homologous end joining of DSBs, 2,3,5,6 53BP1 is also involved in response to viruses, 8 and contributes to replication stress responses by protecting under-replicated genomic loci in G1 phase of the cell cycle. 9,10 Trafficking across the nuclear membrane occurs through nuclear pore complexes (NPCs), large channels consisting of over 30 nucleoporins (NUPs). The central channel of NPC is filled with hydrophobic phenylalanine-glycine (FG) repeats contained in many NUPs, which mediate mostly low-affinity interactions with nuclear transport factors. NUP153 is also an FG-repeat containing NUP, but contains a high-affinity site for importin-b. 11,12 NUP15...

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Section: Discussionmentioning

confidence: 99%

Nucleoporin NUP153 guards genome integrity by promoting nuclear import of 53BP1

et al. 2011

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“…For example, although we do not observe obvious ARL13B accumulation in any potential donor membranes, we cannot rule out the possibility that a small subset of ARL13B localizes to the donor membrane, sorts INPP5E, and mediates INPP5E trafficking from the donor membrane to the ciliary base. Another interesting possibility is related to INPP5E interacting proteins involved in the DNA damage response (DDR) pathway (CEP164, DDB1, IPO4, RUVBL1, and RUVBL2) (36,51). Mutations in CEP164 cause defects in the DDR pathway in addition to ciliogenesis defects.…”

Section: Discussionmentioning

confidence: 99%

ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting

Humbert

Weihbrecht

Searby

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

223

283

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Mutations affecting ciliary components cause a series of related genetic disorders in humans, including nephronophthisis (NPHP), Joubert syndrome (JBTS), Meckel-Gruber syndrome (MKS), and Bardet-Biedl syndrome (BBS), which are collectively termed "ciliopathies." Recent protein-protein interaction studies combined with genetic analyses revealed that ciliopathy-related proteins form several functional networks/modules that build and maintain the primary cilium. However, the precise function of many ciliopathyrelated proteins and the mechanisms by which these proteins are targeted to primary cilia are still not well understood. Here, we describe a protein-protein interaction network of inositol polyphosphate-5-phosphatase E (INPP5E), a prenylated protein associated with JBTS, and its ciliary targeting mechanisms. INPP5E is targeted to the primary cilium through a motif near the C terminus and prenyl-binding protein phosphodiesterase 6D (PDE6D)-dependent mechanisms. Ciliary targeting of INPP5E is facilitated by another JBTS protein, ADP-ribosylation factor-like 13B (ARL13B), but not by ARL2 or ARL3. ARL13B missense mutations that cause JBTS in humans disrupt the ARL13B-INPP5E interaction. We further demonstrate interactions of INPP5E with several ciliary and centrosomal proteins, including a recently identified ciliopathy protein centrosomal protein 164 (CEP164). These findings indicate that ARL13B, INPP5E, PDE6D, and CEP164 form a distinct functional network that is involved in JBTS and NPHP but independent of the ones previously defined by NPHP and MKS proteins.photoreceptor degeneration | retinitis pigmentosa | leber congenital amaurosis | polydactyly | cystic kidney P rimary cilia are microtubule-based cell surface projections that emanate from the centrosome. This subcellular organelle functions as an antenna, sensing and transducing extracellular signals into the cell, and plays an essential role in regulating multiple cellular processes including the cell cycle, embryonic development, and tissue homeostasis (1-3). Mutations affecting ciliary and centrosomal components underlie a group of related human disorders such as Joubert syndrome (JBTS), Meckel-Gruber syndrome (MKS), nephronophthisis (NPHP), and Bardet-Biedl syndrome (BBS), collectively termed ciliopathies (1-3). Recent proteinprotein interaction studies have identified several functional modules or networks involved in these ciliopathies (4). For example, BBS proteins and intraflagellar transport (IFT) proteins form multiprotein complexes, the BBSome and the IFT complexes, respectively, and these complexes are involved in transporting ciliary proteins. Likewise, NPHP and MKS proteins form a distinct modular complex at the transition zone of primary cilia and regulate ciliary membrane compositions (5-9). However, there are many ciliary and centrosomal proteins [e.g., inositol polyphosphate-5-phosphatase E (INPP5E) and ADP-ribosylation factor-like 13B (ARL13B)] that have not been linked to any of the known functional networks and their precise functions ...

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“…Although far from complete, the diverse effects illustrated in the above list suggest that almost anything can result from C/EBPδ binding to a target promoter. Furthermore, a non-transcriptional function for C/EBPδ has also been discovered: it chaperones the FANCD2 DNA repair protein into the nucleus 41. FANCD2 has also been shown to interact with the transcription factor NFκB and to inhibit as well as activate gene expression 42, 43.…”

Section: C/ebpδ As a Versatile Modulator Of Gene Transcriptionmentioning

confidence: 99%

“…By virtue of nuclear localization signals in its DNA-binding domain, C/EBPδ is primarily a nuclear protein, which is translocated at least in part by the IPO4 importin 41. However, C/EBPδ's nuclear localization can be regulated.…”

Section: Regulation Of C/ebpδ Expression and Activitymentioning

confidence: 99%

“…For example, TNF-α not only induces C/EBPδ expression, but also promotes its nuclear accumulation in the adult rat hepatocyte cell line RALA255-10G 63. C/EBPδ's nuclear translocation is augmented by the DNA-damaging agent mitomycin C 41. Billiard et al demonstrated that a flag-tagged C/EBPδ protein is constitutively nuclear in rat calvarial osteoblasts, but the endogenous protein is cytoplasmic in the absence of PGE 2 64.…”

Section: Regulation Of C/ebpδ Expression and Activitymentioning

confidence: 99%

See 1 more Smart Citation

The Many Faces of C/EBPδ and their Relevance for Inflammation and Cancer

Balamurugan

Sterneck²

2013

Int. J. Biol. Sci.

Self Cite

137

143

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The CCAAT/enhancer binding protein delta (CEBPD, C/EBPδ) is a transcription factor that modulates many biological processes including cell differentiation, motility, growth arrest, proliferation, and cell death. The diversity of C/EBPδ's functions depends in part on the cell type and cellular context and can have opposing outcomes. For example, C/EBPδ promotes inflammatory signaling, but it can also inhibit pro-inflammatory pathways, and in a mouse model of mammary tumorigenesis, C/EBPδ reduces tumor incidence but promotes tumor metastasis. This review highlights the multifaceted nature of C/EBPδ's functions, with an emphasis on pathways that are relevant for cancer and inflammation, and illustrates how C/EBPδ emerged from the shadow of its family members as a fascinating “jack of all trades.” Our current knowledge on C/EBPδ indicates that, rather than being essential for a specific cellular process, C/EBPδ helps to interpret a variety of cues in a cell-type and context-dependent manner, to adjust cellular functions to specific situations. Therefore, insights into the roles and mechanisms of C/EBPδ signaling can lead to a better understanding of how the integration of different signaling pathways dictates normal and pathological cell functions and physiology.

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

Cited by 39 publications

References 38 publications

Nucleoporin NUP153 guards genome integrity by promoting nuclear import of 53BP1

Nucleoporin NUP153 guards genome integrity by promoting nuclear import of 53BP1

ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting

The Many Faces of C/EBPδ and their Relevance for Inflammation and Cancer

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