Nucleolar Matrix Metalloproteinase‐2 Regulates rRNA Transcription
Bibliographic record
Abstract
Gene expression in eukaryotic cells is a tightly regulated process, from pre‐transcriptional through post‐transcriptional stages. A major control point in gene expression is ribosome synthesis, since it executes mRNA translation and also regulates their stability. Genes encoding ribosomal proteins and ribosomal RNA (rRNA) are physically located and transcribed in specialized structures within the nucleus known as nucleoli. We previously reported that the protease matrix metalloproteinase‐2 (MMP‐2) was located inside the nucleus but its role there remains elusive. Confocal microscopy studies in our lab showed an accumulation of MMP‐2 in nucleoli in U‐2OS human osteosarcoma cells, suggesting a role in rRNA transcription. We found that MMP‐2 co‐localizes with nucleoli markers fibrillarin and nucleophosmin, and is located in active rRNA transcription sites within nucleoli of U‐2OS cells pulsed with 5‐fluorouridine (5‐FU). Chromatin immunoprecipitation (ChIP) assays showed an enrichment of MMP‐2 in the rRNA gene promoter region. We also found evidence of MMP‐2‐mediated proteolysis of purified histones (H1, H2A, H2B, H3 and H4), in a concentration‐dependent manner. Interestingly, we identified histone H3 to be the most susceptible to MMP‐2 activity and found at least one MMP‐ 2 cleavage site in the N‐terminal tail of histone H3. The N‐terminal tail of histone H3 is the location of a large number of known post‐translational modifications that are involved in the regulation of DNA relaxation and transcription, RNA splicing and DNA repair. Emerging evidence indicates that one of the mechanisms behind this is the proteolytic removal of the N‐terminal tail of histone H3 by a yet uncharacterized protease. Therefore, we sought to elucidate if nucleolar MMP‐2 has proteolytic activity on recombinant histone H3. We incubated MMP‐2 immunoprecipitated from isolated nucleoli with recombinant histone H3, in presence or absence of the MMP‐2 preferring inhibitor ARP‐100. Our data revealed that nucleolar MMP‐2 has proteolytic activity on histone H3 and is sensitive to ARP‐ 100. The involvement of MMP‐2 in rRNA gene expression in the nucleolus is a major novel mechanism by which intracellular may MMP‐2 regulate cell function via histone proteolysis. Support or Funding Information Canadian Institutes of Health Research (CIHR) grants FDN‐143299 (to RS) and MOP‐119515 (to MH) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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 | 0.001 |
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".