Abstract
RNA-binding proteins (RBPs) associate with the primary, precursor, and mature microRNAs, which in turn control post-transcriptional gene regulation. Here, by small RNAseq, we show that RBP FXR1 controls the expression of a subset of mature miRNAs, including highly expressed miR301a-3p in oral cancer cells. We also confirm that FXR1 controls the stability of miR301a-3p. Exoribonuclease PNPT1 degrades miR301a-3p in the absence of FXR1 in oral cancer cells, and the degradation is rescued in the FXR1 and PNPT1 co-knockdown cells. In vitro, we show that PNPT1 is unable to bind and degrade the miRNA once the FXR1-miRNA complex forms. Both miR301a-3p and FXR1 cooperatively target the 3'-UTR of p21 mRNA to promote its degradation. Thus, our work illustrates the unique role of FXR1 that is critical for the stability of a subset of mature miRNAs or at least miR301a-3p to target p21 in oral cancer.
Highlights
RNA-binding proteins (RBPs) regulate co- and post-transcriptional gene expression
Through Fragile X Mental Retardation protein-1 (FXR1)-mediated small RNA sequencing, we unexpectedly found that FXR1 stabilizes miR301a-3p, which in turn targets tumor suppressor p21 and blocks its expression in oral cancer cells. miR301a-3p level goes down in the absence of FXR1, increasing p21 to suppress the growth of oral cancer cells
We provide evidence that miR301a-3p expression is rescued by downregulation of both FXR1 and exoribonuclease PNPT1 in oral cancer cells suggesting that FXR1 acts as a stabilizing factor for miR301a-3p against PNPT1
Summary
RNA-binding proteins (RBPs) regulate co- and post-transcriptional gene expression. RBP Fragile X Mental Retardation protein-1 (FXR1) is involved in the transport, translation, and degradation of mRNA, and often functions by binding either AU-rich elements (ARE) or G-quartet (Gq) regions on the RNA [1,2,3]. FXR1 belongs to the Fragile X-mental retardation (FXR) family of proteins, including FMRP/FMR1 and FXR2 [4]. The proteins share the same RNA binding domains (two KH domains and the RGG box), along with a nuclear localization signal (NLS) and a nuclear export signal (NES) [5]. In addition to RNA-binding activity, FXR family of proteins associate with free ribosomes and polyribosomes [6]. FXR1 is mostly localized in the cytoplasm [4], but like many RBPs, it can shuttle between cytoplasm and nucleus [7]
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