Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway
Bibliographic record
Abstract
// Koji Ando 1,* , Ankur K. Shah 1,* , Vibhu Sachdev 1 , Benjamin P. Kleinstiver 2,3 , Julian Taylor-Parker 1 , Moira M. Welch 2 , Yiheng Hu 4 , Ravi Salgia 5 , Forest M. White 6 , Jeffrey D. Parvin 4 , Al Ozonoff 7 , Lucia E. Rameh 8 , J. Keith Joung 2,3 and Ajit K. Bharti 1 1 Department of Medicine, Division of Hematology Oncology, Boston University School of Medicine, Boston, MA, USA 2 Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA, USA 3 Department of Pathology, Harvard Medical School, Boston, MA, USA 4 Department of Biomedical Informatics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 5 Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte , CA, USA 6 Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA 7 Center for Patient Safety and Quality Research, Boston Children’s Hospital, Boston, MA, USA 8 Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, MA, USA * These authors have contributed equally to this work Correspondence to: Ajit K Bharti, email: // Keywords : topoisomerase I, BRCA1, DNAPK, PTEN, ubiquitin proteasome pathway Received : February 17, 2017 Accepted : March 03, 2017 Published : March 18, 2017 Abstract Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. A higher basal level of topoI-pS10 ensures rapid topoI degradation leading to CPT resistance. Importantly, PTEN regulates DNA-PKcs kinase activity in this pathway and PTEN deletion ensures DNA-PKcs dependent higher topoI-pS10, rapid topoI degradation and CPT resistance.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 | 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 | 0.000 | 0.000 |
| 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".