Abstract
The nucleolus is an important organelle that is responsible for the biogenesis of ribosome RNA (rRNA) and ribosomal subunits assembly. It is also deemed to be the center of metabolic control, considering the critical role of ribosomes in protein translation. Perturbations of rRNA synthesis are closely related to cell proliferation and tumor progression. Telomeric repeat-binding factor 2 (TRF2) is a member of shelterin complex that is responsible for telomere DNA protection. Interestingly, it was recently reported to localize in the nucleolus of human cells in a cell-cycle-dependent manner, while the underlying mechanism and its role on the nucleolus remained unclear. In this study, we found that nucleolar and coiled-body phosphoprotein 1 (NOLC1), a nucleolar protein that is responsible for the nucleolus construction and rRNA synthesis, interacted with TRF2 and mediated the shuttle of TRF2 between the nucleolus and nucleus. Abating the expression of NOLC1 decreased the nucleolar-resident TRF2. Besides, the nucleolar TRF2 could bind rDNA and promoted rRNA transcription. Furthermore, in hepatocellular carcinoma (HCC) cell lines HepG2 and SMMC7721, TRF2 overexpression participated in the nucleolus stress-induced rRNA inhibition and cell-cycle arrest.
Highlights
The function of gene is regulated in many ways, including protein production, modification, distribution, and degradation[1,2], among which the regulation of protein distribution between different subcellular organelles is one important way[3,4,5]
We further identified the colocalization of endogenous Telomeric repeat-binding factor 2 (TRF2) and Nucleolar and coiled-body phosphoprotein 1 (NOLC1) in HEK293T (Fig. 1d and Figure S1A) and hepatoma carcinoma cell SMMC7721 (Figure S1B, first line), but not in cervical cancer HeLa cells (Figure S1B, second line), which was consistent with our previous findings, we have not found a reasonable explanation so far for the cell-line differences
We detected the distribution of NOLC1 and TRF2 with upstream-binding factor (UBF), a nucleolus marker, which further convinced that TRF2 was mostly localized in the nucleolus (Fig. 1e and Figure S1C)
Summary
The function of gene is regulated in many ways, including protein production, modification, distribution, and degradation[1,2], among which the regulation of protein distribution between different subcellular organelles is one important way[3,4,5]. The sub-organelles regulation role of the nucleolus, a eukaryotic subnuclear organelle, which is responsible for ribosomal RNA transcription, processing, modification, and ribosomes assembly, was recently reported frequently[6,7,8]. Accumulating evidences have linked this organelle to many other aspects except for ribosome RNA (rRNA) metabolism, leading to the concept of plurifunctional nucleolus[9,10,11,12,13,14]. Ubiquitylation NOLC1 could drive the formation of a treacle ribosome biogenesis factor 1 (TCOF1)-NOLC1 platform that remodeled the translational program of differentiating cells in favor of neural crest specification[22], and it could act as a transcriptional regulator and activated the alpha-1-acid glycoprotein (agp) in mammalian livers[23].
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