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bioRxiv · 10.1101/2025.01.09.632225

Nucleolar Stress-inducing Compounds Influence rDNA occupancy of RNA Polymerase I Transcription Machinery

Yglesias, M. V.·DeRose, V. J.
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Abstract

Transcription of ribosomal RNA (rRNA) by RNA Polymerase I (Pol I) is often upregulated in cancer to facilitate rapid cell growth and proliferation, and has emerged as a potential target for chemotherapeutic agents. BMH-21 and Pt(II) chemotherapeutic agent oxaliplatin are well documented as inhibitors of Pol I activity, however the underlying mechanisms for this inhibition are not completely understood. Here, we applied chromatin immunoprecipitation sequencing (ChIP-seq) techniques and immunofluorescence imaging to probe the influence of oxaliplatin and BMH-21 on Pol I machinery. We demonstrate oxaliplatin and BMH-21 induce early nucleolar stress leading to the formation of "nucleolar caps" containing Pol I and upstream binding factor (UBF) which corresponds with broad reductions in ribosomal DNA (rDNA) occupancy of Pol I. Distinct occupancy patterns for the two compounds are revealed in ChIP-seq experiments. Taken together, our findings suggest that in vivo, oxaliplatin does not induce Pol I inhibition via interrupting a specific step in Pol I transcription, while treatment with BMH-21 induced unique polymerase stalling at the promoter and terminator regions of the human ribosomal RNA gene.

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Yglesias, M. V., DeRose, V. J.. 2025-01-09. Nucleolar Stress-inducing Compounds Influence rDNA occupancy of RNA Polymerase I Transcription Machinery. https://doi.org/10.1101/2025.01.09.632225

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