Structural insight into how WDR4 promotes the tRNA N7-methylguanosine methyltransferase activity of METTL1
Xiaohuan Jin, Zeyuan Guan, Na Hu, C.-X. He, Ping Yin, Zhou Gong, Delin Zhang
Abstract
N7-methylguanosine (m 7 G) at position 46 of the tRNA variable loop is among the most prevalent posttranscriptional tRNA modifications in prokaryotes and eukaryotes, and plays crucial roles in the stability and function of tRNAs 1 , 2 , 3 . In mammals, tRNA m 7 G46 modifications are installed by methyltransferase-like 1 (METTL1) and its cofactor WD repeat domain 4 (WDR4) 4 . WDR4 is indispensable for maintaining normal METTL1 protein levels and the function of METTL1–WDR4 complexes, as depletion of WDR4 decreases METTL1 expression and tRNA m 7 G modification levels 5 , 6 . Recent studies have revealed that METTL1 or WDR4 deficiency abolishes m 7 G tRNA modification and results in a variety of disorders, including impaired embryonic stem cell self-renewal and differentiation 7 , microcephalic primordial dwarfism and Galloway-Mowat syndrome 8 , 9 , 10 . Additionally, METTL1 and WDR4 are upregulated in a variety of cancer cells and regulate the translation of oncogenes and cell-cycle related mRNAs in an m 7 G tRNA-decoded codon-dependent manner to promote tumor progression 5 , 6 , 11 , 12 . However, the mechanism by which WDR4 regulates the function of METTL1 remains elusive, which limits drug development for m 7 G-related cancers and other diseases.