PHF3 binds G-rich RNAs and regulates RNA stability through its TFIIS-like domain (TLD) and plant homeodomain (PHD)

ABSTRACT: Transcription and RNA processing are tightly coupled and precisely coordinated to ensure appropriate levels of mature transcripts. The C-terminal domain (CTD) of RNA polymerase II (Pol II) is phosphorylated differentially during the transcription cycle and serves as a landing pad for a variety of transcriptional regulators and RNA processing proteins. PHD finger protein 3 (PHF3) binds to the serine-2 phosphorylated Pol II CTD with its Spen Paralogue and Orthologue C-terminal (SPOC) domain and regulates transcription elongation and mRNA stability. Here we show that PHF3 is an RNA-binding protein that recognizes a G-rich motif prone to form G-quadruplexes (G4s) within RNAs required for neurogenesis. We identify PHF3 TFIIS-like domain (TLD) as an RNA-binding domain, which shows nanomolar affinity for G-rich RNAs. TLD recruits PHF3 onto target RNAs and acts in concert with the plant homeodomain (PHD) to promote target RNA destabilization. PHF3 SPOC and PHD-TLD domains mediate interactions with various RNA-binding proteins (RBPs) that regulate mRNA stability. While PHF3 SPOC-dependent interactions with the m6A writer complex, splicing and elongation factors do not impact m6A RNA modification, alternative splicing or polyadenylation, PHF3 PHD-TLD domains interact with the PAF1 complex as a positive regulator of mRNA stability and interfere with its binding to Pol II. Our results establish PHF3 as an RNA-binding protein that binds G-rich RNAs through its TLD domain and destabilizes RNAs through PHD-TLD domains.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278179 | GEO | 2025/09/26

REPOSITORIES: GEO