The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention

Kathryn E. Pendleton, Beibei Chen, Kuanqing Liu, Olga V. Hunter, Yang Xie, Benjamin P. Tu, Nicholas K. Conrad

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

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 small nuclear RNA (snRNA). These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.

Original languageEnglish (US)
Pages (from-to)824-835.e14
JournalCell
Volume169
Issue number5
DOIs
StatePublished - May 18 2017

Fingerprint

Methionine Adenosyltransferase
S-Adenosylmethionine
Methyltransferases
Introns
3' Untranslated Regions
Vertebrates
Small Nuclear RNA
Biological Phenomena
Methylation
Starvation
Methionine
Adenosine
Homeostasis
Maintenance
U6 small nuclear RNA methyltransferase
U6 small nuclear RNA
Substrates

Keywords

  • alternative splicing
  • Intron retention
  • MAT2A
  • methionine
  • METTL16
  • N6-methyladenosine (mA)
  • RNA methylation
  • S-adenosylmethionine (SAM)
  • SAM metabolism
  • U6 snRNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. / Pendleton, Kathryn E.; Chen, Beibei; Liu, Kuanqing; Hunter, Olga V.; Xie, Yang; Tu, Benjamin P.; Conrad, Nicholas K.

In: Cell, Vol. 169, No. 5, 18.05.2017, p. 824-835.e14.

Research output: Contribution to journalArticle

Pendleton, Kathryn E. ; Chen, Beibei ; Liu, Kuanqing ; Hunter, Olga V. ; Xie, Yang ; Tu, Benjamin P. ; Conrad, Nicholas K. / The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. In: Cell. 2017 ; Vol. 169, No. 5. pp. 824-835.e14.
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