Histidine N1-position-specific methyltransferase CARNMT1 targets C3H zinc finger proteins and modulates RNA metabolism

• Published in: Genes & development Vol. 37; no. 15-16; pp. 724 - 742
• Main Authors: Shimazu, Tadahiro, Yoshimoto, Rei, Kotoshiba, Kaoru, Suzuki, Takehiro, Matoba, Shogo, Hirose, Michiko, Akakabe, Mai, Sohtome, Yoshihiro, Sodeoka, Mikiko, Ogura, Atsuo, Dohmae, Naoshi, Shinkai, Yoichi
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01-08-2023
• Subjects: Animals; Carnosine; Histidine - genetics; Methyltransferases - genetics; Mice; Mice, Inbred C3H; Research Papers; RNA Precursors; RNA Splice Sites; Zinc Fingers; methyltransferase; CARNMT1; embryonic lethality; embryonic development; methylation; zinc finger protein; U2AF1; degradation; mRNA; splicing; histidine
• ISSN: 0890-9369; 1549-5477; 1549-5477
• DOI: 10.1101/gad.350755.123

Histidine (His) residues are methylated in various proteins, but their roles and regulation mechanisms remain unknown. Here, we show that carnosine N-methyltransferase 1 (CARNMT1), a known His methyltransferase of dipeptide carnosine (βAla-His), is a major His N1-position-specific methyltransferase. We found that 52 His sites in 20 proteins underwent CARNMT1-mediated methylation. The consensus methylation site for CARNMT1 was identified as Cx(F/Y)xH, a C3H zinc finger (C3H ZF) motif. CARNMT1-deficient and catalytically inactive mutant mice showed embryonic lethality. Among the CARNMT1 target C3H ZF proteins, RNA degradation mediated by Roquin and tristetraprolin (TTP) was affected by CARNMT1 and its enzymatic activity. Furthermore, the recognition of the 3' splice site of the CARNMT1 target C3H ZF protein U2AF1 was perturbed, and pre-mRNA alternative splicing (AS) was affected by CARNMT1 deficiency. These findings indicate that CARNMT1-mediated protein His methylation, which is essential for embryogenesis, plays roles in diverse aspects of RNA metabolism by targeting C3H ZF-type RNA-binding proteins and modulating their functions, including pre-mRNA AS and mRNA degradation regulation.