RNA-binding proteins (RBPs) are a class of key effectors of gene expression. Recent application of RNA interactome capture (RIC) technology has enabled the identification of over 2000 human proteins implicated in RNA binding. However, many of these newly discovered proteins lack known RNA-binding domains and remain unvalidated as bona fide RBPs. Comprehensive characterization of these RBP candidates thus holds promise to uncover new RBPs that may serve as drivers of cancer development or therapeutic targets for cancer treatment.
In a study published in Nucleic Acis Research, a team led by Prof. Hui Jingyi from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences characterized the understudied GPATCH4 as an oncogenic RBP in hepatocellular carcinoma (HCC) and revealed a new mechanism by which it functions as a regulator of nucleolar R-loops to control rRNA transcription through interacting with DDX21.
This study systematically searched for altered RBP candidates in HCC through multi-omics data integrative analyses and identified that GPATCH4 gene is amplified in over 70% HCC patients and its high expression predicts poor prognosis. GPATCH4 is a member of G-patch domain-containing family. Researchers mapped the in vivo RNA binding sites of GPATCH4 by iCLIP-seq and characterized that GPATCH4 primarily bound ribosomal RNA (rRNAs).
Results from in vivo and in vitro biochemical assays indicate that GPATCH4 is a bona fide RBP and prefers to bind GC-rich sequences in rRNAs. GPATCH4 promoted HCC cell proliferation and transformation both in vitro and in vivo through increasing rRNA transcription and global protein synthesis. GPATCH4 is mainly localized in the nucleolus and maintains nucleolar homeostasis in a G-patch motif-independent manner in HCC cells. It helps to unwind R-loops formed at the rDNA through interacting with DDX21 via its C-terminal intrinsically disordered region (IDR). Removal of accumulated R-loops induced by GPATCH4 depletion rescued decreased rRNA transcription and cell proliferation.
Taken together, this study uncovered a molecular mechanism through which GPATCH4 executes pro-cancer effect by R-loop-mediated control of rRNA transcription. In cancer, Pol I transcription is frequently upregulated to meet the elevated demands for ribosome production in rapidly proliferating cells. Findings in this study suggest that targeting this pathway‒ either by inhibiting Pol I activity by small molecule inhibitors or reducing GPATCH4 expression ‒ represents a potential therapeutic strategy for HCC patients with GPATCH4 amplification.
Reference: https://academic.oup.com/nar/article/53/10/gkaf438/8140458
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