Abstract GMM-027: DYNLL1 INHIBITS DNA END RESECTION IN BRCA1-DEFICIENT CELLS AND REGULATES PARP INHIBITOR SENSITIVITY
Bibliographic record
Abstract
Abstract High-grade serous ovarian carcinoma (HGSOC) patients with germline mutations in BRCA1/2 exhibit high sensitivity and improved outcome to double strand DNA break (DSB)-inducing agents [i.e. platinum and Poly(ADP-ribose) polymerase inhibitors (PARPi)] due to underlying defects in DNA repair via homologous recombination (HR). Due to their effectiveness, three PARP inhibitors (olaparib, rucaparib, niraparib) have recently gained FDA approval for the treatment of HGSOCs. However, de novo and acquired resistance to these agents is common even in the BRCA mutation carriers, and pose a significant, and unsolved, clinical challenge. Therefore, we adopted a systematic approach to comprehensibly identify unexplored factors/pathways that could be responsible for PARPi/platinum resistance in BRCA-defective HGSOC patients. Here we identify DYNLL1 as a negative regulator of DNA end resection through a loss-of-function CRISPR screen in BRCA1-mutant ovarian carcinoma cells. DNA end resection is a vital process that initiates homologous recombination (HR)-mediated repair of double-stranded DNA breaks (DSBs), and consequently influences genome stability. In BRCA-defective HGSOC patients, DNA end resection is greatly compromised and contribute to the loss of HR and PARP inhibitor sensitivity. Loss of DYNLL1 allows DNA end resection and restores HR in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and PARP inhibitors. In primary ovarian carcinomas low BRCA1 expression correlates with increased chromosomal aberrations, and the junction sequences of somatic structural variants indicate the loss of HR. Concurrent decrease in DYNLL1 expression in BRCA1 low ovarian cancers ‘rescued' this phenotype with reduced genomic alterations and increased homology at putative lesions. DYNLL1 limits nucleolytic degradation of DNA ends by interacting with the DNA end resection machinery (MRN complex, BLM helicase and DNA2) in cells. The impact of DYNLL1 on end resection can be re-capitulated in vitro and this is dependent on direct interaction with MRE11. In the absence of exogenous stress, depletion of DYNLL1 slows DNA replication fork progression due to ectopic activity of MRE11. Therefore, we infer that DYNLL1 is an important anti-resection factor that significantly influences genomic stability and response to DNA damaging chemotherapy. Citation Format: Yizhou Joseph He, Khyati Meghani, Marie-Christine Caron, Chunyu Yang, Daryl A. Ronato, Jie Bian, Anchal Sharma, Jessica Miller, Niraj Joshi, Alexandre Detappe, John G. Doench, Gaelle Legube, David E. Root, Alan D. D'Andrea, Pascal Drané, Subhojyoti De, Panagiotis Konstantinopoulos, Jean-Yves Masson, and Dipanjan Chowdhury. DYNLL1 INHIBITS DNA END RESECTION IN BRCA1-DEFICIENT CELLS AND REGULATES PARP INHIBITOR SENSITIVITY [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-027.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".