Abstract A27: Assessing somatic tumor-associated RAD51 mutations and screening for novel dominant-interfering RAD51 proteins
Bibliographic record
Abstract
Abstract The responsiveness of cancer cells to chemotherapy and targeted treatment, as well as the development of resistance, is determined by the state of DNA damage response pathways. Homology-directed repair (HDR) is crucial for error-free repair of DNA double-strand breaks that arise during replication stress or are induced by exogenous genotoxins. Therefore, HDR efficacy status in cancer cells could potentially be utilized as an indicator to predict tumor responsiveness to standard chemotherapies and to poly(ADP-ribose) polymerases (PARP) inhibitors. We are interested in understanding the influence of different levels of functional activity of the HDR pathway on treatment responses. To this end, we have investigated the functional consequence of RAD51 point mutations identified in tumors. RAD51 is an effector of the key tumor suppressor BRCA2 and contributes to genome integrity in actively dividing cells. RAD51 mutations are identified from Memorial Sloan Kettering clinical sequencing cohort (MSK-IMPACT), the Catalogue of Somatic Mutations in Cancer (COSMIC) and the International Fanconi Anemia Registry (IFAR). To understand the implications of these altered residues on RAD51 function in HDR, we tested repair efficiency using a previously established DR-GFP reporter assay in mammalian cells. Of eighteen novel RAD51 mutants examined, ten displayed decreased HDR efficiency, three had wild-type levels of HDR, and five had increased HDR levels. To test whether the HDR-deficient RAD51 mutants lead to sensitivity to genotoxins, we assayed the survival of corn smut U. maydis that expressed these RAD51 mutants after treatment with DNA damaging agents ultraviolet light, diepoxybutane, or methylmethane sulfonate. All ten HDR-defective mutants were found to be sensitive to one or more genotoxins. In addition, six were found to promote sensitivity to DNA damaging agents when they were expressed in wild-type cells—i.e., a dominant negative phenotype. Interestingly, these dominant negative mutants confer selective sensitivity to specific DNA damaging agent(s). The underlying mechanism is still under investigation; nevertheless, these mutations can be used as biomarkers for HDR efficiency and to identify novel interactions of RAD51. The identification of these somatic tumor-associated RAD51 mutants warrants further testing for sensitivity towards chemotherapy drugs such as PARP inhibitors and gemcitabine. Furthermore, a random mutagenesis screening is in progress to identify more novel dominant negative RAD51 mutations. The functional analysis of RAD51 is critical as readouts for HDR efficiency, which impacts personalized chemotherapeutic choices. The result of this study will hopefully expand the benefits of using PARP inhibitors not just on BRCA1/2- and RAD51 paralog-deficient tumors but also on tumors with RAD51 mutations. Citation Format: Pei Xin Lim, Jeanette Sutherland, Raymond Noonan, Alexandra Dananberg, William Holloman, Agata Smogorzewska, Maria Jasin. Assessing somatic tumor-associated RAD51 mutations and screening for novel dominant-interfering RAD51 proteins [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 A27.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 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".