Smith, Eric A, Gole, Boris, Willis, Nicholas A, Soria, Rebeca, Starnes, Linda M, Krumpelbeck, Eric F, Jegga, Anil G, Ali, Abdullah M, Guo, Haihong, Meetei, Amom R et al (show 7 more authors)
(2017)
DEK is required for homologous recombination repair of DNA breaks.
SCIENTIFIC REPORTS, 7 (1).
44662-.
Abstract
DEK is a highly conserved chromatin-bound protein whose upregulation across cancer types correlates with genotoxic therapy resistance. Loss of DEK induces genome instability and sensitizes cells to DNA double strand breaks (DSBs), suggesting defects in DNA repair. While these DEK-deficiency phenotypes were thought to arise from a moderate attenuation of non-homologous end joining (NHEJ) repair, the role of DEK in DNA repair remains incompletely understood. We present new evidence demonstrating the observed decrease in NHEJ is insufficient to impact immunoglobulin class switching in DEK knockout mice. Furthermore, DEK knockout cells were sensitive to apoptosis with NHEJ inhibition. Thus, we hypothesized DEK plays additional roles in homologous recombination (HR). Using episomal and integrated reporters, we demonstrate that HR repair of conventional DSBs is severely compromised in DEK-deficient cells. To define responsible mechanisms, we tested the role of DEK in the HR repair cascade. DEK-deficient cells were impaired for γH2AX phosphorylation and attenuated for RAD51 filament formation. Additionally, DEK formed a complex with RAD51, but not BRCA1, suggesting a potential role regarding RAD51 filament formation, stability, or function. These findings define DEK as an important and multifunctional mediator of HR, and establish a synthetic lethal relationship between DEK loss and NHEJ inhibition.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Hela Cells, Animals, Mice, Knockout, Humans, DNA-Binding Proteins, Oncogene Proteins, Chromosomal Proteins, Non-Histone, Histones, Protein Kinase Inhibitors, Apoptosis, DNA Repair, Protein Binding, Radiation, Ionizing, Female, Male, Rad51 Recombinase, Replication Protein A, DNA Breaks, Double-Stranded, Homologous Recombination, Poly-ADP-Ribose Binding Proteins |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 12 Feb 2019 10:06 |
| Last Modified: | 19 Jan 2023 01:04 |
| DOI: | 10.1038/srep44662 |
| Open Access URL: | https://doi.org/10.1038/srep44662 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3032547 |
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