Aberrant Translation Regulated By METTL1/WDR4-Mediated tRNA N 7-Methylguanosine Modification Drives DLBCL Progression

Abstract

Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N 7 - methylguanosine (m 7G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in diffuse large B-cell lymphoma (DLBCL) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting DLBCL cell survival and progression using loss- and gain-of-function assays in vivo. Mechanistically, m 7G tRNA modification selectively regulates the translation of oncogenic transcripts, in m 7G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m 7G tRNA modification in promoting DLBCL tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m 7G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.