Pendleton Kathryn E, Chen Beibei, Liu Kuanqing, Hunter Olga V, Xie Yang, Tu Benjamin P, Conrad Nicholas K
Department of Microbiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Cell. 2017 May 18;169(5):824-835.e14. doi: 10.1016/j.cell.2017.05.003.
Maintenance of proper levels of the methyl donor S-adenosylmethionine (SAM) is critical for a wide variety of biological processes. We demonstrate that the N-adenosine methyltransferase METTL16 regulates expression of human MAT2A, which encodes the SAM synthetase expressed in most cells. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhanced splicing of a retained intron. Induction requires METTL16 and its methylation substrate, a vertebrate conserved hairpin (hp1) in the MAT2A 3' UTR. Increasing METTL16 occupancy on the MAT2A 3' UTR is sufficient to induce efficient splicing. We propose that, under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, which promotes MAT2A splicing. We further show that METTL16 is the long-unknown methyltransferase for the U6 spliceosomal small nuclear RNA (snRNA). These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.
维持甲基供体S-腺苷甲硫氨酸（SAM）的适当水平对于多种生物过程至关重要。我们证明，N-腺苷甲基转移酶METTL16调节人类MAT2A的表达，MAT2A编码大多数细胞中表达的SAM合成酶。在蛋氨酸饥饿导致SAM耗竭时，细胞通过增强保留内含子的剪接来诱导MAT2A表达。诱导需要METTL16及其甲基化底物，即MAT2A 3'UTR中的脊椎动物保守发夹结构（hp1）。增加METTL16在MAT2A 3'UTR上的占据足以诱导高效剪接。我们提出，在SAM限制条件下，由于酶促周转效率低下，METTL16在hp上的占据增加，从而促进MAT2A剪接。我们进一步表明，METTL16是U6剪接体小核RNA（snRNA）长期未知的甲基转移酶。这些观察结果表明，保守的U6 snRNA甲基转移酶在脊椎动物中进化出了一种额外的功能来调节SAM稳态。
