ArticleNucleic acids research2016
DDK dependent regulation of TOP2A at centromeres revealed by a chemical genetics approach.
Article in Nucleic acids research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 49 citations in OpenAlex.
- Exploring the multifaceted Dbf4-dependent kinase from temporal, spatial, and substrate repertoire perspectives.Communications biology · 2026Review
- A comprehensive atlas of epigenetic regulators reveals tissue-specific epigenetic regulation patterns.Epigenetics · 2023Article
- A machine learning framework develops a DNA replication stress model for predicting clinical outcomes and therapeutic vulnerability in primary prostate cancer.Journal of translational medicine · 2023Article
- ZFP281-BRCA2 prevents R-loop accumulation during DNA replication.Nature communications · 2022Article
- DNA topoisomerase II alpha promotes the metastatic characteristics of glioma cells by transcriptionally activating β-catenin.Bioengineered · 2022Article
- Identification of Human Cell Cycle Phase Markers Based on Single-Cell RNA-Seq Data by Using Machine Learning Methods.BioMed research international · 2022Article
- Cdc7-mediated phosphorylation of Cse4 regulates high-fidelity chromosome segregation in budding yeast.Molecular biology of the cell · 2021Article
- Exploration of the Role of the C-Terminal Domain of Human DNA Topoisomerase IIα in Catalytic Activity.ACS omega · 2021Article
- Propofol modulates the proliferation, invasion and migration of bladder cancer cells through the miR‑145‑5p/TOP2A axis.Molecular medicine reports · 2021Article
- Sharp Downregulation of Hub Genes Associated With the Pathogenesis of Breast Cancer From Ductal CarcinomaFrontiers in oncology · 2021Article
- Development of a novel gene signature to predict prognosis and response to PD-1 blockade in clear cell renal cell carcinoma.Oncoimmunology · 2021Article
- Identification of differentially expressed protein-coding genes in lung adenocarcinomas.Experimental and therapeutic medicine · 2020Article
- TOP2A Promotes Cell Migration, Invasion and Epithelial-Mesenchymal Transition in Cervical Cancer via Activating the PI3K/AKT Signaling.Cancer management and research · 2020Article
- Overlapping Roles in Chromosome Segregation for Heterochromatin Protein 1 (Swi6) and DDK inGenetics · 2019Article
- Primary neurons can enter M-phase.Scientific reports · 2019Article
- Cdc7-Dbf4-mediated phosphorylation of HSP90-S164 stabilizes HSP90-HCLK2-MRN complex to enhance ATR/ATM signaling that overcomes replication stress in cancer.Scientific reports · 2017Article
- Review
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In eukaryotic cells the CDC7/DBF4 kinase, also known as DBF4-dependent kinase (DDK), is required for the firing of DNA replication origins. CDC7 is also involved in replication stress responses and its depletion sensitises cells to drugs that affect fork progression, including Topoisomerase 2 poisons. Although CDC7 is an important regulator of cell division, relatively few substrates and bona-fide CDC7 phosphorylation sites have been identified to date in human cells. In this study, we have generated an active recombinant CDC7/DBF4 kinase that can utilize bulky ATP analogues. By performing in vitro kinase assays using benzyl-thio-ATP, we have identified TOP2A as a primary CDC7 substrate in nuclear extracts, and serine 1213 and serine 1525 as in vitro phosphorylation sites. We show that CDC7/DBF4 and TOP2A interact in cells, that this interaction mainly occurs early in S-phase, and that it is compromised after treatment with CDC7 inhibitors. We further provide evidence that human DBF4 localises at centromeres, to which TOP2A is progressively recruited during S-phase. Importantly, we found that CDC7/DBF4 down-regulation, as well S1213A/S1525A TOP2A mutations can advance the timing of centromeric TOP2A recruitment in S-phase. Our results indicate that TOP2A is a novel DDK target and have important implications for centromere biology.
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