Functional and genetic interactions of Mus81 with the Chk2-p53 tumor suppressor pathway
Bibliographic record
Abstract
The progression of a normal cell to a cancer cell is thought to involve the acquisition of several mutations that result in unregulated proliferation, improper differentiation, and increased survival phenotypes. Much of classical cancer research has focused on searching for novel genes that contribute to either tumor suppression or oncogenesis. However, since multiple mutational hits are required to drive cancer, studying the interaction and cooperation of genes in cancer progression and suppression may provide models that more accurately depict human carcinogenesis and provide new therapeutical insights. In yeast and mammalian cells, the Mus8l endonuclease plays a role in DNA repair and recombination by cleaving branched DNA substrates such as replication forks, 3'DNA flaps, and Holliday Junctions. To study the in vivo functions of mammalian Mus81, our lab generated Mus81 -/- mice, Mus81-/- mice are viable and fertile but are extremely sensitive to the interstrand crosslinking agent MMC. Significantly, Mus81+/- and Mus81-/- cells display spontaneous chromosomal damage and Mus81+/- and Mus81 -/- mice are susceptible to spontaneous tumorigenesis. These findings have identified Mus8l as an important caretaker of the genome and established it as a candidate haploinsufficient tumor suppressor. The focus of this thesis is the investigation of the genetic interplay between Mus81 and the Chk2-p53 tumor suppressor pathway in DNA repair responses and tumor suppression. This thesis demonstrates that p53 plays a critical role in eliminating damaged Mus81-/- cells. Furthermore, our findings demonstrate that dual inactivation of Mus81 and p53 results in a synergistic increase in genomic instability, accelerated tumorigenesis, and a profound predisposition for sarcoma development. Thus, Mus81 inactivation may play a critical role in human sarcoma development. Contrastingly, we found that Chk2 does not participate in eliminating DNA damaged Mus81-/- cells. Furthermore, loss of Chk2 results in a rescue of the genomic instability inherent in Mus81-/- mice and remarkably rescues the tumor susceptibility of Mus81-/- mice. Thus, our study suggests that in response to DNA damage in Mus81-/- cells, Chk2 does not mimic p53 as a gatekeeper and tumor suppressor, but instead promotes oncogenesis.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".