Abstract B025: A genome-wide CRISPR screen identifies synthetic lethality of double-stranded RNA with BRCA1 loss
Bibliographic record
Abstract
Abstract Double-stranded RNAs (dsRNAs) are potent immunostimulatory nucleic acids of viral origin but also physiologically produced by mammalian cells. Recent studies demonstrated that elevating dsRNA levels, either exogenously through dsRNA mimetics like Polyinosinic-polycytidylic acid (pI:C) or endogenously through epigenetic modulation of retroviral elements, can elicit anticancer effects. In response to dsRNA, cells elicit a dual response consisting in Interferon (IFN) production and translational shutdown associated, in some cells, with cell death. These two responses are linked in a feed-forward loop in which induced cytokines themselves enhance dsRNA sensing by the death-inducing pathway, complicating our understanding of the cell-intrinsic mechanisms at play. The 2',5'-oligoadenylate synthetase (OAS)-RNASEL system is widely thought to be the main responsible for dsRNA-induced cell death, but it remains unclear how its activity leads to cell death. To elucidate these mechanisms, we decided to minimize the impact of interferon modulation by studying dsRNA-induced death in interferon-saturated conditions. We performed a genome-wide CRISPR screen for factors involved in dsRNA-induced death in our interferon-saturated conditions in HT29 cells. Pathway enrichment analysis of screen hits revealed that RNA surveillance, RNA Polymerase II Transcription Initiation, Mitochondrial translation and respiratory chain and DNA Repair genes have a protective role against dsRNA increase. In particular, we identifiedBRCA1 but not BRCA2 as a candidate hit. The differential sensitivity of BRCA1-KO cells was subsequently validated in cloncal populations. Ongoing research is aimed at validating this interaction in vivo models. Our work shed light on potential new mechanisms involved in dsRNA dependent cell death, revealing a connection with DNA damage and BRCA1. If confirmed, these findings may pave the way for the use of dsRNA mimetics, possibly in conjunction with immune checkpoint inhibitors, in the treatment of BRCA1-mutated tumors. Citation Format: Luca Mazzarella, Deborah Trastulli, Sara Galavotti, Gianluca Vozza, Veronica Pinamonti, Nunzia Zagaria. A genome-wide CRISPR screen identifies synthetic lethality of double-stranded RNA with BRCA1 loss [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B025.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".