Abstract A04: Cross-species analysis identifies MUS81, a structure-specific endonuclease, as a novel synthetic lethal interaction with PARP
Bibliographic record
Abstract
Abstract Recently, the inhibition of poly ADP-ribose polymerase, or PARP, in BRCA-mutated cells has been exploited as a therapeutic strategy for cancer due to the strong PARP/BRCA synthetic lethal relationship. Evidence suggests this lethality is likely due to DNA repair defects; however, details of this mechanism remain unclear. To this end, we sought to identify a larger spectrum of genes whose mutation renders cells sensitive to PARP inhibition. Using the model organism Caenorhabditis elegans, we developed an in vivo variomics approach to screen mutated C. elegans strains for sensitivity to the PARP inhibitor olaparib. Multiple sensitive strains contained mutations in either mus-81 or eme-1, two genes that form a heterodimeric DNA endonuclease complex involved in both stalled fork cleavage in replication and Holliday junction resolution in homologous recombination repair. Further investigation revealed that olaparib treatment caused somatic proliferation defects and anaphase bridges in mus-81 mutants. We found the MUS81/PARP genetic interaction from C. elegans to be conserved in human cells. Compared to MUS81 wild-type cell lines, MUS81 knockout cells showed a significant decrease in proliferation after exposure to PARP inhibitor and had characteristics distinct from olaparib-treated BRCA2 knockout cells. Surprisingly, cells that were lacking MUS81 and treated with PARP inhibitor showed a lack of apoptosis, dramatic increase in tetraploidy and higher incidence of anaphase bridges in mitosis. Using cross-species approaches, we have identified a new PARP synthetic lethal interaction that is conserved in human cells. Our results suggest that MUS81 protection after PARP inhibitor treatment is functionally distinct from other homologous recombination repair genes and provides further insights into the mechanism behind PARP inhibitor-induced selective tumor cell killing. Citation Format: Melanie L. Bailey, Nigel J. O’Neil, Philip Hieter. Cross-species analysis identifies MUS81, a structure-specific endonuclease, as a novel synthetic lethal interaction with PARP [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A04.
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 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 | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".