Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Corresponding author
Pedro Henrique Costa Cruz
Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
Izumi Nagatomo
Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
Yuki Kato
Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka 565-0871, Japan
Daisuke Motooka
Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
Shingo Satoh
Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
Yuichi Adachi
Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
Yoshito Takeda
Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
Yukio Kawahara
Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka 565-0871, Japan; Corresponding author
Atsushi Kumanogoh
Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Department of Immunopathology, World Premier Institute Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka 565-0871, Japan; Corresponding author
Summary: 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.
