PubMed · 5066721
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K Minoda. 1972. [Retinoblastoma].. https://pubmed.ncbi.nlm.nih.gov/5066721/
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The nucleolus is essential for ribosome biogenesis and cellular homeostasis, and its dysfunction can induce nucleolar stress, a process implicated in cancer and other diseases. However, nucleolar stress is commonly inferred from morphological changes or a limited set of functional assays, and quantitative approaches based on gene expression profiles remain lacking. Here, we integrate literature curation with multi-dataset screening to define a nucleolar stress gene signature and develop a nucleolar stress score (NuS) applicable to bulk transcriptomics, single-cell transcriptomics, proteomics, and spatial transcriptomics. Using this framework, we show in colorectal cancer models that oxaliplatin induces nucleolar stress, suppresses nascent rRNA synthesis, and activates p53 signaling, whereas these responses are attenuated in oxaliplatin-resistant cells. Combined with a ribosome biogenesis activity score (RiboSis), NuS captures related but distinct dimensions of nucleolar function and stratifies tumors into functional states associated with clinical outcomes. NuS-based analysis of perturbational transcriptomes further prioritizes compounds with putative nucleolar stress-inducing activity. Collectively, this study provides a quantitative framework for evaluating nucleolar stress and illustrates its applications in disease stratification and drug mechanism discovery.
RNA polymerase II carboxy terminal domain (CTD) kinases are key elements in the control of mRNA synthesis. Yeast CTD kinase I (CTDK-I), is a non-essential complex involved in the regulation of mRNA synthesis at the level of transcription elongation, pre-mRNA 3' formation and nuclear export. Here, we report that CTDK-I is also involved in ribosomal RNA synthesis. We show that CTDK-I is localized in part in the nucleolus. In its absence, nucleolar structure and RNA polymerase I transcription are affected. In vitro experiments show an impairment of the Pol I transcription machinery. Remarkably, RNA polymerase I co-precipitates from cellular extracts with Ctk1, the kinase subunit of the CTDK-I complex. In vitro analysis further demonstrates a direct interaction between RNA polymerase I and Ctk1. The results suggest that CTDK-I might participate in the regulation of distinct nuclear transcriptional machineries, thus playing a role in the adaptation of the global transcriptional response to growth signalling.
Upon completion of mitosis, daughter nuclei assemble all of the organelles necessary for the implementation of nuclear functions. We found that upon entry into daughter nuclei, snRNPs and SR proteins do not immediately colocalize in nuclear speckles. SR proteins accumulated in patches around active nucleolar organizing regions (NORs) that we refer to as NOR-associated patches (NAPs), whereas snRNPs were enriched at other nuclear regions. NAPs formed transiently, persisting for 15-20 min before dissipating as nuclear speckles began to form in G1. In the absence of RNA polymerase II transcription, NAPs increased in size and persisted for at least 2 h, with delayed localization of SR proteins to nuclear speckles. In addition, SR proteins in NAPs are hypophosphorylated, and the SR protein kinase Clk/STY colocalizes with SR proteins in NAPs, suggesting that phosphorylation releases SR proteins from NAPs and their initial target is transcription sites. This work demonstrates a previously unrecognized role of NAPs in splicing factor trafficking and nuclear speckle biogenesis.