Abstract 2979: Tumor suppressor ING1b maintains genomic stability through PCNA monoubiquitination and histone H4 acetylation
Bibliographic record
Abstract
Abstract Unrepaired lesion on DNA template blocks replication fork progression and causes replication stress. Prolonged stalling of replication may give rise to serious consequences such as replication collapse, DNA double strand breaks (DSBs), recombination and genomic instability. The lesion bypass pathway, which is regulated by PCNA monoubiquitination, is essential for resolving replication stalling. We demonstrated a novel tumor suppressive function of p33ING1b (ING1b) in preserving genomic stability upon replication stress. We found that ING1b knockdown cells exhibit defects in S phase recovery and enhanced genomic instability due to UV-induced replication blockage. We showed that ING1b is required for PCNA monoubiquitination upon replication stress. Enhanced PCNA monoubiquitination due to overexpression of the E3 ligase Rad18 or knockdown of the deubiquitinating enzyme USP1 is abrogated in ING1b depleted cells. Furthermore, ING1b is required for Rad18 foci formation, localization to chromatin and interaction with PCNA after UV. In addition, ING1b is required for foci formation of Polη, a translesion DNA polymerase, indicating that ING1b is involved in regulation of the lesion bypass mechanism. We found that ING1b depleted cells display hypoacetylation of histone H4 at S phase and treatment with class I and II histone deacetylase inhibitors restores histone H4 acetylation and PCNA monoubiquitination in ING1b knockdown cells. These data suggest that ING1b regulates PCNA monoubiquitination through histone H4 acetylation to facilitate lesion bypass and recovery from replication blockage. This provides insights into a novel mechanism regulating lesion bypass through chromatin remodeling in maintaining genomic stability upon replication stress. It has implications in developing new strategies for cancer prevention and treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2979.
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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) | 0.003 | 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".