Role of CUX1 DNA repair function in the resistance of cancer cells to ionizing radiation
Bibliographic record
Abstract
More than 50% of cancer patients are treated with radiotherapy.Unfortunately, cancer cells driven by a RAS oncogene exhibit resistance to radiotherapy.Previous studies established that CUX1 knockdown is synthetic lethal to cancer cells carrying a RAS oncogene.The decrease in viability following CUX1 knockdown was associated with an increase in oxidative DNA damage.Mechanistically, the Cut repeat domains within p200 CUX1 were found to stimulate the enzymatic activities of the 8-oxoguanine DNA glycosylase 1 (OGG1) and the apurinic/apyrimidinic endonuclease 1 (APE1), two enzymes of the base excision repair (BER) pathway involved in the repair of oxidized bases and apurinic/apyrimidinic (AP) sites, respectively.In agreement with these results, repair of oxidative DNA damage is accelerated following ectopic p200 CUX1 expression and delayed after CUX1 knockdown.Since oxidized bases and apurinic/apyrimidinic (AP) sites are produced by ionizing radiation, we hypothesized that CUX1 may contribute to the resistance of cancer cells to ionizing radiation through its function as an accessory factor for OGG1 and APE1.In turn, inhibition of CUX1 DNA repair activity would sensitize cancer cells to ionizing radiation.To validate CUX1 as a therapeutic target, we initiated a series of experiments to test the effect of CUX1 knockdown and overexpression on the resistance of cancer cells to ionizing radiation.The goal of my project was to choose and optimize the assays that would enable us to perform these experiments.In parallel, I performed preliminary experiments to investigate the effects of CUX1 knockdown and overexpression on the resistance of cancer cells to ionizing radiation and other treatments that increase oxidative DNA damage.After optimizing the methyl-14 C thymidine incorporation assay and the single-cell gel electrophoresis (comet) assay, I observed across a panel of tumour cell lines that CUX1 knockdown sensitizes cancer cells to radiations and to an agent causing oxidative DNA damage (TH588c), whereas CUX1 overexpression confers radio-resistance.Importantly, a recombinant CUX1 protein containing only two Cut repeats (CR1CR2) is devoid of transcriptional activity, but is still able to stimulate DNA repair and confer radio-resistance.Similarly, OGG1 overexpression confers radio-resistance to DLD-1 colorectal cells, but not to "normal" retinal pigment epithelial cells (RPE1), whereas OGG1 knockdown sensitizes both DLD-1 and U251 glioblastoma cells to radiations.My work will help establish the proof-ofprinciple that Cut repeat domains represent a valuable therapeutic target in sensitizing tumor cells to radiotherapy. Mr. Lam Leduy:He generated all cell lines mentioned in this study, with the exception of MDA-MB-231 plxsn vector +/-p200 CUX1, plenti vector +/-CR1CR2, and MCF-7 plenti vector +/-CR1CR2.He performed immunoblots of HCT116 in Fig. 26A and U87 and T98G in Fig. 26B.Dr. Zubaidah Ramdzan: She generated Figure 6 and 17.She transfected the DLD-1 and U251 cell lines with siOGG1 and performed the experiments with me in Figures 16B, 18, 22, and 25: D-E and I-J.She also performed the HCT116 shCUX1 clonogenic assay in Fig. 19.Ms. Priya Aneja: She performed the comet assays in Fig. 11, and assisted in performing comet assays in Fig. 12.
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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 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 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".