A cancer-associated METTL14 mutation induces aberrant m6A modification, affecting tumor growth

Abstract

The methyltransferase-like 3 (METTL3)-/METTL14-containing complex predominantly catalyzes N⁶-methyladenosine (m6A) modification, which affects mRNA stability. Although the METTL14 R298P mutation is found in multiple cancer types, its biological effects are not completely understood. Here, we show that the heterozygous R298P mutation promotes cancer cell proliferation, whereas the homozygous mutation reduces proliferation. Methylated RNA immunoprecipitation sequencing analysis indicates that the R298P mutation reduces m6A modification at canonical motifs. Furthermore, this mutation induces m6A modification at aberrant motifs, which is evident only in cell lines harboring the homozygous mutation. The aberrant recognition of m6A modification sites alters the methylation efficiency at surrounding canonical motifs. One example is c-MET mRNA, which is highly methylated at canonical motifs close to the aberrantly methylated sites. Consequently, c-MET mRNA is severely destabilized, reducing c-Myc expression and suppressing cell proliferation. These data suggest that the METTL14 R298P mutation affects target recognition for m6A modification, perturbing gene expression patterns and cell growth.

Keywords: CP: Cancer; CP: Molecular biology; METTL14; MeRIP-seq; RNA methylation; c-MET; c-Myc; endometrial cancer; m6A; mutational hotspot.