image: FuHsi, a novel nucleolar protein, enhances rDNA transcription and tumor progression by orchestrating the assembly and stability of the rDNA transcription initiation complex.
Credit: ©Science China Press
The nucleolus serves as the central hub for ribosomal DNA (rDNA) transcription and ribosome biogenesis, processes essential for protein synthesis and cellular proliferation. rDNA transcription is tightly controlled by a well-defined machinery, including RNA Polymerase I (Pol I), upstream binding factor (UBF), selectivity factor 1 (SL1), and treacle ribosome biogenesis factor 1 (TCOF1). While long non-coding RNAs (lncRNAs) are known to encode functional microproteins that regulate diverse cellular pathways, their potential roles in nucleolar function remain largely unexplored.
In a groundbreaking study, Yang et al. combined LC-MS/MS-based nucleolar proteomics with a microprotein database to identify seven candidate microproteins. Among these, the lncRNA DLGAP1-AS2 stood out due to its broad expression in normal tissues and frequent upregulation in cancers. The team confirmed that DLGAP1-AS2 encodes an 88-amino acid nucleolar microprotein, which they named FuHsi (after the mythical creator Fu Xi, symbolizing its fundamental role in rDNA transcription and nucleolar biogenesis).
FuHsi depletion leads to severe defects in rRNA synthesis, ribosomal subunit assembly, and rDNA transcription activity. The microprotein physically interacts with core components of the rDNA transcription machinery, including RPA194, UBF, TBP, and TCOF1, forming an essential part of the transcriptional apparatus. Strikingly, FuHsi exhibits a unique hierarchical position in the transcription complex - while its presence is required for the proper recruitment of other transcription factors to rDNA loci, its own binding remains independent of these factors. This distinctive property suggests that FuHsi may serve as the first molecule that orchestrates the assembly and stability of the rDNA transcription initiation complex.
The clinical significance of DLGAP1-AS2/FuHsi is underscored by its frequent overexpression in lung adenocarcinoma, where elevated expression levels correlate with poorer patient outcomes. Functionally, FuHsi drives oncogenic progression, as evidenced by the potent suppression of tumor growth upon its depletion. These findings establish DLGAP1-AS2/FuHsi as both a promising prognostic indicator and a potential therapeutic target for cancers characterized by dysregulated ribosome biogenesis.
This study reveals FuHsi as a paradigm-shifting lncRNA-encoded microprotein that fundamentally regulates nucleolar rDNA transcription. By occupying a unique, upstream position in the transcription complex hierarchy, FuHsi represents a novel class of regulatory factors governing ribosome biogenesis. The discovery of its oncogenic properties opens new avenues for targeting the nucleolar transcription machinery in cancer therapy, while providing fresh insights into the complex regulation of cellular growth and proliferation.
Journal
Science Bulletin