Mettl1-dependent m7G tRNA modification is essential for maintaining spermatogenesis and fertility in Drosophila melanogaster
Shunya Kaneko, Keita Miyoshi, Kotaro Tomuro, Makoto Terauchi, Ryoya Tanaka, Shu Kondo, Naoki Tani, Kei‐ichiro Ishiguro, Atsushi Toyoda, Azusa Kamikouchi, Hideki Noguchi, Shintaro Iwasaki, Kuniaki Saito
Abstract
Modification of guanosine to N7-methylguanosine (m7G) in the variable loop region of tRNA is catalyzed by the METTL1/WDR4 heterodimer and stabilizes target tRNA. Here, we reveal essential functions of Mettl1 in Drosophila fertility. Knockout of Mettl1 (Mettl1-KO) causes no major effect on the development of non-gonadal tissues, but abolishes the production of elongated spermatids and mature sperm, which is fully rescued by expression of a Mettl1-transgene, but not a catalytic-dead Mettl1 transgene. This demonstrates that Mettl1-dependent m7G is required for spermatogenesis. Mettl1-KO results in a loss of m7G modification on a subset of tRNAs and decreased tRNA abundance. Ribosome profiling shows that Mettl1-KO led to ribosomes stalling at codons decoded by tRNAs that were reduced in abundance. Mettl1-KO also significantly reduces the translation efficiency of genes involved in elongated spermatid formation and sperm stability. Germ cell-specific expression of Mettl1 rescues disrupted m7G tRNA modification and tRNA abundance in Mettl1-KO testes but not in non-gonadal tissues. Ribosome stalling is much less detectable in non-gonadal tissues than in Mettl1-KO testes. These findings reveal a developmental role for m7G tRNA modification and indicate that m7G modification-dependent tRNA abundance differs among tissues. Here the authors reveal essential functions of Mettl1, catalyzing N7-guanosine methylation (m7G) of tRNAs, in Drosophila male fertility through a regulation of the steady-state level of tRNAs and the translational efficiency of genes essential for spermatogenesis.