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Large-scale RNA-binding protein tethering screen discovers modulators of circular RNA metabolism [tethering_screen_LARP4B_RIP_eCLIP]

ABSTRACT: Circular RNAs (circRNAs), formed by back-splicing in mammalian cells, are increasingly recognized for their roles in various biological processes and their potential in RNA therapeutics. However, the RNA-binding proteins (RBPs) that regulate circRNAs throughout their lifecycle remain largely unknown. Here, we present the most comprehensive evaluation to date, assessing 730 RBPs for their potential to regulate circRNAs. Using both luciferase-based and qPCR assays, we uncover a range of potential regulatory mechanisms. We identify 296 RBPs that encompass diverse components of circRNA metabolism including biogenesis, nuclear export, translation and degradation. Our findings show that LARP4B universally enhances circRNA translation, while ANXA2 enhances circRNA translation in a cell type-specific manner, shedding light on advancing circRNA therapeutic vector design. Moreover, we identify RBM15 as a multifaceted regulator of circRNAs, promoting their biogenesis via interactions with SRSF proteins and retaining circRNAs in the nucleus through RNA-dependent interactions with IGF2BP1. Notably, RBM15 binds directly to exonic regions near back-splicing junctions, and is a conserved RBP regulator of circRNA biogenesis. These insights advance our understanding of the trans-regulators in circRNA biogenesis and metabolism and offer new avenues for RNA therapeutic development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314432 | GEO | 2026/08/28

REPOSITORIES: GEO

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