Deficiency in a glutamine-specific methyltransferase for release factor causes mouse embryonic lethality.
Biological methylation is a fundamental enzymatic reaction for a variety of substrates in multiple cellular processes. Mammalian N6amt1 was thought to be a homologue of bacterial N(6)-adenine DNA methyltransferases, but its substrate specificity and physiological importance remain elusive. Here, we demonstrate that N6amt1 functions as a protein methyltransferase for the translation termination factor eRF1 in mammalian cells both in vitro and in vivo. Mass spectrometry analysis indicated that about 70% of the endogenous eRF1 is methylated at the glutamine residue of the conserved GGQ motif. To address the physiological significance of eRF1 methylation, we disrupted the N6amt1 gene in the mouse. Loss of N6amt1 led to early embryonic lethality. The postimplantation development of mutant embryos was impaired, resulting in degeneration around embryonic day 6.5. This is in contrast to what occurs in Escherichia coli and Saccharomyces cerevisiae, which can survive without the N6amt1 homologues. Thus, N6amt1 is the first glutamine-specific protein methyltransferase characterized in vivo in mammals and methylation of eRF1 by N6amt1 might be essential for the viability of early embryos.
Liu
Peng
P
The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Nie
Song
S
Li
Bing
B
Yang
Zhong-Qiang
ZQ
Xu
Zhi-Mei
ZM
Fei
Jian
J
Lin
Chyuansheng
C
Zeng
Rong
R
Xu
Guo-Liang
GL
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000378:metabolism* / Q000648:ultrastructure; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010454:Peptide Termination Factors / Q000378:metabolism; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific)
D010454:Peptide Termination Factors; D005973:Glutamine; D008780:Methyltransferases; C511868:PRED28 protein, mouse; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific)