The human DEK oncogene regulates DNA damage response signaling and repair

Kavanaugh, Gina M.; Wise‐Draper, Trisha M.; Morreale, Richard J.; Morrison, Monique; Gole, Boris; Schwemberger, Sandy; Tichy, Elisia D.; Lu, Lu; Babcock, George F.; Wells, James M.; Drissi, Rachid; Bissler, John J.; Stambrook, Peter J.; Andreassen, Paul R.; Wiesmüller, Lisa; Wells, Susanne I.

doi:10.1093/nar/gkr454

Cited by 84 publications

(103 citation statements)

References 48 publications

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“…To this end, DEK was overexpressed in NIKS using a previously published 30 retroviral vector shown to be functional in vitro. 37 DEK was expressed to a level comparable to that observed in cancer cells (Fig. S2A).…”

Section: Dek Protein Levels Are Drastically Reduced In Mitotic Cellssupporting

confidence: 59%

“…While nocodazole clearly arrests cells in mitosis it is also known to cause DNA damage [58][59][60][61] , and DEK contributes to DNA damage repair. 37 Thus DEK may be retained on chromatin in nocodazole treated cells in order to support the DNA damage response and repair. Furthermore, we have observed instances wherein endogenous DEK is retained on mitotic chromosomes, and these may also be related to DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…37 MEFs were maintained in high glucose DMEM (http://www.lifetechnologies.com/order/catalog/product/11965118) containing 10% FBS, 2 mM L-glutamine (http://cellgro.com/ products/cell-culture-reagents/amino-acids-vitamins/L-glutamineliquid-2.html), 100 mM MEM non-essential amino acids (https:// www.lifetechnologies.com/order/catalog/product/11140050), 0.055 mM b-mercaptoethanol (Midwest Scientific-0482-1) and 10 mg/ml gentamycin (http://www.lifetechnologies.com/order/catalog/product/15710064). Spontaneously immortalized near-diploid human keratinocyte cell line (NIKS) 45 were maintained in Fmedia, which is 3 parts Dulbecco's modified Eagle's medium to 1 part Ham's F12 media (https://www.lifetechnologies.com/order/ catalog/product/11765070) supplemented with the following components: 5% fetal bovine serum, 24 ug/ml adenine, 8.4 ng/ml cholera toxin (http://www.labome.com/product/EMD-Millipore/ 227036-1MG.html), 10 ng/ml epidermal growth factor (http://www.sigmaaldrich.com/catalog/product/sigma/ e4127), 2.4 mg/ml hydrocortisone (http://www.sigmaaldrich.com/catalog/ product/sigma/h0888), 5 mg/ml insulin, 1% penicillin-streptomycin (https:// www.lifetechnologies.com/order/catalog/ product/15140122), and 0.2% fungizone (http://www.omegascientific.com/ shop/fungizone-amphotericin-b/).…”

Section: Methodsmentioning

confidence: 99%

“…[28][29][30][31][32] During interphase, DEK plays a role in numerous nuclear processes including transcription, RNA processing, DNA repair, and chromatin organization. 20,[33][34][35][36][37] DEK is a highly modified protein, containing 57 potential phosphorylated sites and over 70 lysine residues with the potential to be poly ADPribosylated and ubiquitinated. 26,27,[38][39][40] Such modifications alter its ability to bind chromatin, re-localize, and carry out specific biological functions in a manner that remain poorly understood and have been studied primarily in cancer cells wherein DEK is over-expressed.…”

Section: Introductionmentioning

confidence: 99%

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DEK over-expression promotes mitotic defects and micronucleus formation

Matrka

Hennigan

Kappes³

et al. 2015

Cell Cycle

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The DEK gene encodes a nuclear protein that binds chromatin and is involved in various fundamental nuclear processes including transcription, RNA splicing, DNA replication and DNA repair. Several cancer types characteristically over-express DEK at the earliest stages of transformation. In order to explore relevant mechanisms whereby DEK supports oncogenicity, we utilized cancer databases to identify gene transcripts whose expression patterns are tightly correlated with that of DEK. We identified an enrichment of genes involved in mitosis and thus investigated the regulation and possible function of DEK in cell division. Immunofluorescence analyses revealed that DEK dissociates from DNA in early prophase and re-associates with DNA during telophase in human keratinocytes. Mitotic cell populations displayed a sharp reduction in DEK protein levels compared to the corresponding interphase population, suggesting DEK may be degraded or otherwise removed from the cell prior to mitosis. Interestingly, DEK overexpression stimulated its own aberrant association with chromatin throughout mitosis. Furthermore, DEK colocalized with anaphase bridges, chromosome fragments, and micronuclei, suggesting a specific association with mitotically defective chromosomes. We found that DEK over-expression in both non-transformed and transformed cells is sufficient to stimulate micronucleus formation. These data support a model wherein normal chromosomal clearance of DEK is required for maintenance of high fidelity cell division and chromosomal integrity. Therefore, the overexpression of DEK and its incomplete removal from mitotic chromosomes promotes genomic instability through the generation of genetically abnormal daughter cells. Consequently, DEK over-expression may be involved in the initial steps of developing oncogenic mutations in cells leading to cancer initiation

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Section: Dek Protein Levels Are Drastically Reduced In Mitotic Cellssupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

DEK over-expression promotes mitotic defects and micronucleus formation

Matrka

Hennigan

Kappes³

et al. 2015

Cell Cycle

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“…Upregulation of DEK was involved in the p53/mouse double minute, B-cell lymphoma 2 family, and caspase signaling pathways (26). Notably, certain studies have revealed that DEK expression is associated with resistance to chemotherapeutic drugs, such as camptothecin, etoposide, neocarzinostatin and doxorubicin, which is often used to treat breast cancer (21,27,28).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of DEK is an indicator of poor prognosis in patients with gastric adenocarcinoma

Xia

Kong

et al. 2016

Oncology Letters

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Abstract. Increased expression of the human DEK proto-oncogene (DEK) gene has been associated with numerous human malignancies. The DEK protein is associated with chromatin reconstruction and gene transcription, and is important in cell apoptosis. The present study aimed to elucidate the role of DEK with regard to gastric adenocarcinoma tumor progression and patient prognosis. DEK protein expression was analyzed using immunohistochemistry in 192 tumors paired with adjacent non-cancerous gastric mucosa that had been surgically resected from patients with primary gastric adenocarcinoma. The association between DEK expression and the clinicopathological characteristics of the patients was evaluated using the χ 2 test and Fisher's exact test. The survival rates of the patients were calculated using the Kaplan-Meier method. Cox analysis evaluated the association between the expression of DEK and the survival rate of the patients. The DEK protein was expressed in 84 patients with gastric adenocarcinoma (43.8%) and in 20 of the paired normal gastric mucosa tissues (11.5%). The DEK expression rate was found to be associated with tumor size (P=0.006), tumor grade (P=0.023), lymph node metastasis (P=0.018), serous invasion (P=0.026), tumor stage (P=0.001) and Ki-67 expression (P=0.003). Furthermore, patients with gastric adenocarcinoma that expressed DEK had decreased disease-free (log-rank, 16.785; P<0.0001) and overall (log-rank, 15.759; P<0.0001) survival rates compared with patients without DEK expression. Patients with late-stage gastric adenocarcinoma that expressed DEK exhibited a lower overall survival rate compared with patients without DEK expression (P=0.002). Additional analysis revealed that DEK expression was an independent prognostic factor for the prognosis of gastric adenocarcinoma (hazard ratio, 0.556; 95% confidence interval, 0.337-0.918; P=0.022). From the results of the present study, it can be concluded that the detection of DEK protein expression in gastric adenocarcinoma tissues may be important for the diagnosis and prognosis of patients, and may be a targeted therapy for the treatment of gastric adenocarcinoma.

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Bacterial Growth Inhibition Screen (BGIS) identifies a loss‐of‐function mutant of the DEK oncogene, indicating DNA modulating activities of DEK in chromatin

et al. 2021

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The DEK oncoprotein regulates cellular chromatin function via a number of protein–protein interactions. However, the biological relevance of its unique pseudo‐SAP/SAP‐box domain, which transmits DNA modulating activities in vitro, remains largely speculative. As hypothesis‐driven mutations failed to yield DNA‐binding null (DBN) mutants, we combined random mutagenesis with the Bacterial Growth Inhibition Screen (BGIS) to overcome this bottleneck. Re‐expression of a DEK‐DBN mutant in newly established human DEK knockout cells failed to reduce the increase in nuclear size as compared to wild type, indicating roles for DEK–DNA interactions in cellular chromatin organization. Our results extend the functional roles of DEK in metazoan chromatin and highlight the predictive ability of recombinant protein toxicity in E. coli for unbiased studies of eukaryotic DNA modulating protein domains.

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The human DEK oncogene regulates DNA damage response signaling and repair

Cited by 84 publications

References 48 publications

DEK over-expression promotes mitotic defects and micronucleus formation

DEK over-expression promotes mitotic defects and micronucleus formation

Overexpression of DEK is an indicator of poor prognosis in patients with gastric adenocarcinoma

Bacterial Growth Inhibition Screen (BGIS) identifies a loss‐of‐function mutant of the DEK oncogene, indicating DNA modulating activities of DEK in chromatin

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