Abstract A10: The impact of cancer-associated RAD51C mutations in homologous recombination
Bibliographic record
Abstract
Abstract Homologous recombination (HR) is a major pathway for the repair of DNA double-strand breaks (DSBs). Loss of function of key HR repair proteins have been linked to diseases characterized by genomic instability including cancers and Fanconi anemia. Regulation of RAD51 filaments is critical during HR repair and is mediated by several factors including the RAD51 paralogs, a group of proteins that share sequence homology with RAD51. The RAD51 paralog family consists of five proteins in humans, RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3. The RAD51 paralog, RAD51C, has recently become a key protein of interest as RAD51C mutations have been linked to familial breast and ovarian cancers. However, the specific functions of RAD51C have remained enigmatic as mouse and non-tumorigenic knockout models are inviable. Given these limitations, we have identified RAD51C point mutations from breast and ovarian cancer patients to study the phenotypes of these RAD51C mutants and how they impair homologous recombination. We have found that RAD51C mutations can disrupt interactions with RAD51 paralog binding partners, RAD51B and XRCC3, required for RAD51C stability. Through yeast-two/three-hybrid and co-immunoprecipitation experiments, we isolated RAD51C mutations that disrupt interactions within RAD51 paralog complexes. These complexes have important roles in the repair of classical DSBs induced by ionizing radiation or chemotherapeutic reagents as well as in replication fork protection such as after replication stress induced by hydroxyurea. Using RAD51C mutants to complement a conditional knockout model, we investigated how the roles of RAD51C were impacted by point mutations in response to these diverse substrates to ultimately understand how tumors with RAD51C mutations can be best targeted for treatment. Citation Format: Meghan R. Sullivan, Rohit Prakash, Maria Jasin, Kara A. Bernstein. The impact of cancer-associated RAD51C mutations in homologous recombination [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A10.
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.011 | 0.002 |
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".