An oncopeptide regulates m6A recognition by the m6A reader IGF2BP1 and tumorigenesis

Song Zhu,Guang-Rong Yan,Nan Meng,Ji-Zhong Wang,Min Chen,De Chen,Rui-Xun Lu,Yu-Tian He,Xiao-Lan Zhang,Xin-Hui Chen

doi:10.1038/s41467-020-15403-9

Abstract

N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic RNAs. The biological importance of m6A relies on m6A readers, which control mRNA fate and function. However, it remains unexplored whether additional regulatory subunits of m6A readers are involved in the m6A recognition on RNAs. Here we discover that the long noncoding RNA (lncRNA) LINC00266-1 encodes a 71-amino acid peptide. The peptide mainly interacts with the RNA-binding proteins, including the m6A reader IGF2BP1, and is thus named “RNA-binding regulatory peptide” (RBRP). RBRP binds to IGF2BP1 and strengthens m6A recognition by IGF2BP1 on RNAs, such as c-Myc mRNA, to increase the mRNA stability and expression of c-Myc, thereby promoting tumorigenesis. Cancer patients with RBRPhigh have a poor prognosis. Thus, the oncopeptide RBRP encoded by LINC00266-1 is a regulatory subunit of m6A readers and strengthens m6A recognition on the target RNAs by the m6A reader to exert its oncogenic functions.

Highlights

N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic RNAs
Knockdown of LINC00266-1 resulted in significant decreases in cell growth, colony formation, migration, and invasion, whereas these alterations were restored to the control level after the addition of open reading frames (ORFs) expression, but not LINC00266-1 MT expression (Fig. 3b–d), indicating that the RNAbinding regulatory peptide” (RBRP) peptide, but not the long noncoding RNA (lncRNA) LINC00266-1 itself, promotes tumorigenesis
IGF2BP1-bound RNAs in wild-type (WT) RBRP-expressed cells had more RNA m6A modification abundance than those in RBRP G19A mutantexpressed cells (Fig. 5g). These results indicate that RBRP increases the binding of IGF2BP1 to m6A-modified c-Myc coding region instability determinant (CRD) mRNA by its G19 residue

Summary

Introduction

N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic RNAs. The biological importance of m6A relies on m6A readers, which control mRNA fate and function. Knockdown of LINC00266-1 resulted in significant decreases in cell growth, colony formation, migration, and invasion, whereas these alterations were restored to the control level after the addition of ORF expression, but not LINC00266-1 MT expression (Fig. 3b–d), indicating that the RBRP peptide, but not the lncRNA LINC00266-1 itself, promotes tumorigenesis.

Results

Conclusion