Abstract PR21: DEK is critical for homologous recombination and its loss is synthetic lethal with DNA-PK inhibition
Bibliographic record
Abstract
Abstract DEK is a highly conserved chromatin-bound protein whose upregulation across different cancer types directly correlates with genotoxic therapy resistance. While DEK loss induces genome instability and sensitizes cells to DNA double strand breaks (DSBs), suggesting defects in DNA repair, the role of DEK remains incompletely understood. To this end we previously determined that loss of DEK moderately attenuates non-homologous end-joining repair (NHEJ). However, the observed partial decrease in NHEJ activity is likely insufficient to fully explain the sensitivity of DEK-deficient cells to radiation and chemotherapy. Thus, we hypothesized that DEK has additional roles in DSB repair, particularly in homologous recombination (HR) DNA repair, a known contributor to chemotherapy resistance. We found that γH2AX activation and HR were strongly compromised in DEK-deficient cells, and that DEK physically interacted with and contributed to RAD51 recruitment. Thus, we hypothesized that DEK-deficient cells likely rely on residual NHEJ for repair of DSBs and survival. Correspondingly, NHEJ inhibition with DNA-PK inhibitors resulted in synthetic lethality in DEK-deficient cells. Together these findings define DEK as an important and multifunctional mediator of homologous recombination. This abstract is also being presented as Poster A09. Citation Format: Eric A. Smith, Boris Gole, Nicholas A. Willis, Krumpelbeck F. Eric, Anil G. Jegga, Abdullah M. Ali, Haihong Guo, Amom R. Meetei, Paul R. Andreassen, Ferdinand Kappes, Ralph Scully, Lisa Wiesmüller, Wells I. Susanne. DEK is critical for homologous recombination and its loss is synthetic lethal with DNA-PK inhibition [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR21.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".