The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention

By Kathryn E. Pendleton, Beibei Chen, Kuanqing Liu, Olga V. Hunter, Yang Xie, B. Tu, N. Conrad. Cell, 2017

996 citations recorded by the source corpus.

SUMMARY Maintenance of proper levels of the methyl donor S-adenosylmethionine (SAM) is critical for a wide variety of biological processes. We demonstrate that the N6-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 snRNA. These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/741069f9d5af37746ab356c97aeffc638a5cfafe

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In Cancer Research

1. Chuan He
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3. Samie R. Jaffrey
4. P. He
5. Hailing Shi
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In Molecular Biology

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Citations in the corpus

• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “…and Structure While the METTL3/14 complex preferentially installs m6A methylation in a sequence motif RRACH (R = A or G; H = A, C, or U) (Liu et al., 2013), another m6A writer, methyltransferase-like 16 (METTL16) installs m6A in a different sequence and structure context (Pendleton et al., 2017).”
• Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “also found that most of the METTL16-dependent m(6)A peaks were in introns or spanned intron-exon boundaries.(6) Several possibilities may explain different conclusions.”
• Functions of N6-methyladenosine and its role in cancer (2019, background): “MAT2A encodes the SAM synthetase.”
• Rethinking m6A Readers, Writers, and Erasers (2017, background): “Conrad and colleagues showed that human METTL16 synthesizes m6A in both human U6 and the U6-like hairpins in MAT2A mRNA (Pendleton et al. 2017).”
• m6A RNA methylation: from mechanisms to therapeutic potential (2021, positive): “…of m 6 A on mRNA is deposited by METTL3/METTL14, the U6 snRNA m 6 A methyltransferase METTL16 has also been reported to catalyze the addition of m 6 A on the structured 3 0 UTR of MAT2A transcripts (Pendleton et al , 2017; Doxtader et al , 2018; Mendel et al , 2018; Ruszkowska et al , 2018).”