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bioRxiv · 10.1101/2020.02.21.958280

Matrix metalloproteinase-2 mediates ribosomal RNA transcription by cleaving nucleolar histones

Ali, M. A. M.·Garcia-Vilas, J. A.·Cromwell, C. R.·Hubbard, B. P.·Hendzel, M. J.·Schulz, R.
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Abstract

Cell proliferation and survival require continuous ribosome biogenesis and protein synthesis. Genes encoding ribosomal RNA (rRNA) are physically located in a specialized substructure within the nucleus known as the nucleolus, which has a central role in the biogenesis of ribosomes. Matrix metalloproteinase-2 (MMP-2) was previously detected in the nucleus. However, its role there is elusive. Herein we report that MMP-2 resides within the nucleolus to regulate rRNA transcription. MMP-2 is enriched at the promoter region of rRNA gene repeats and its inhibition downregulates pre-rRNA transcription. The N-terminal tail of histone H3 is clipped by MMP-2 in the nucleolus and is associated with increased rRNA transcription. Knocking down/out MMP-2 or inhibiting its activity prevents histone H3 cleavage and reduces both rRNA transcription and cell proliferation. In addition to the known extracellular roles of MMP-2 in tumor growth, our data reveal an epigenetic mechanism whereby intranucleolar MMP-2 regulates cell proliferation through histone proteolysis and facilitation of rRNA transcription.

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Ali, M. A. M., Garcia-Vilas, J. A., Cromwell, C. R., Hubbard, B. P., Hendzel, M. J., Schulz, R.. 2020-02-22. Matrix metalloproteinase-2 mediates ribosomal RNA transcription by cleaving nucleolar histones. https://doi.org/10.1101/2020.02.21.958280

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