S-Adenosylmethionine Synthesis Is Regulated by Selective N6-Adenosine Methylation and mRNA Degradation Involving METTL16 and YTHDC1

被引：297

作者：

Shima, Hiroki ^{[1
,2
]}

Matsumoto, Mitsuyo ^{[1
,2
]}

Ishigami, Yuma ^{[3
]}

Ebina, Masayuki ^{[1
]}

Muto, Akihiko ^{[1
]}

Sato, Yuho ^{[1
]}

Kumagai, Sayaka ^{[1
]}

Ochiai, Kyoko ^{[1
,2
]}

Suzuki, Tsutomu ^{[3
]}

Igarashi, Kazuhiko ^{[1
,2
]}

机构：

[1] Tohoku Univ, Dept Biochem, Grad Sch Med, Sendai, Miyagi 9808575, Japan

[2] Tohoku Univ, Ctr Regulatory Epigenome & Dis, Grad Sch Med, Sendai, Miyagi 9808575, Japan

[3] Univ Tokyo, Grad Sch Engn, Dept Chem & Biotechnol, Tokyo 1138656, Japan

来源：

CELL REPORTS | 2017年 / 21卷 / 12期

基金：

日本学术振兴会;

关键词：

EMBRYONIC STEM-CELLS; M(6)A RNA; SACCHAROMYCES-CEREVISIAE; SAM SYNTHETASE; METHIONINE; BINDING; TRANSLATION; GENE; EXPRESSION; COMPLEX;

D O I：

10.1016/j.celrep.2017.11.092

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

S-adenosylmethionine (SAM) is an important metabolite as a methyl-group donor in DNA and histone methylation, tuning regulation of gene expression. Appropriate intracellular SAM levels must be maintained, because methyltransferase reaction rates can be limited by SAM availability. In response to SAM depletion, MAT2A, which encodes a ubiquitous mammalian methionine adenosyltransferase isozyme, was upregulated through mRNA stabilization. SAM-depletion reduced N-6-methyladenosine (m(6)A) in the 3' UTR of MAT2A. In vitro reactions using recombinant METTL16 revealed multiple, conserved methylation targets in the 3' UTR. Knockdown of METTL16 and the m(6)A reader YTHDC1 abolished SAM-responsive regulation of MAT2A. Mutations of the target adenine sites of METTL16 within the 3' UTR revealed that these m(6)As were redundantly required for regulation. MAT2A mRNA methylation by METTL16 is read by YTHDC1, and we suggest that this allows cells to monitor and maintain intracellular SAM levels.

引用

页码：3354 / 3363

页数：10

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