VIRMA mediates preferential m6A mRNA methylation in 3′UTR and near stop codon and associates with alternative polyadenylation

By Y. Yue, Jun Liu, X. Cui, Jie Cao, Guanzheng Luo, Zezhou Zhang, T. Cheng, Minsong Gao, Xiao Shu, Honghui Ma and 7 more. Cell Discovery, 2018

847 citations recorded by the source corpus.

N6-methyladenosine (m6A) is enriched in 3′untranslated region (3′UTR) and near stop codon of mature polyadenylated mRNAs in mammalian systems and has regulatory roles in eukaryotic mRNA transcriptome switch. Significantly, the mechanism for this modification preference remains unknown, however. Herein we report a characterization of the full m6A methyltransferase complex in HeLa cells identifying METTL3/METTL14/WTAP/VIRMA/HAKAI/ZC3H13 as the key components, and we show that VIRMA mediates preferential mRNA methylation in 3′UTR and near stop codon. Biochemical studies reveal that VIRMA recruits the catalytic core components METTL3/METTL14/WTAP to guide region-selective methylations. Around 60% of VIRMA mRNA immunoprecipitation targets manifest strong m6A enrichment in 3′UTR. Depletions of VIRMA and METTL3 induce 3′UTR lengthening of several hundred mRNAs with over 50% targets in common. VIRMA associates with polyadenylation cleavage factors CPSF5 and CPSF6 in an RNA-dependent manner. Depletion of CPSF5 leads to significant shortening of 3′UTR of over 2800 mRNAs, 84% of which are modified with m6A and have increased m6A peak density in 3′UTR and near stop codon after CPSF5 knockdown. Together, our studies provide insights into m6A deposition specificity in 3′UTR and its correlation with alternative polyadenylation.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fd7449c317b2a3730d4b5624039698c3d51b7ab7

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In Molecular Biology

1. Chuan He
2. Hailing Shi
3. Jiangbo W
4. Phillip J Hsu
5. Ying Yang
6. Yu-Sheng Chen
7. Yun-Gui Yang
8. Huayan Duan

Citations in the corpus

• UniProt: a worldwide hub of protein knowledge (2018, background): “…work. m 6 A methylation is performed by a heteromeric WMM N 6 -adenosine-methyltransferase complex, originally thought to be a heterotrimer of METTL3 (UniPro-tKB:Q86U44), METTL14 (UniProtKB:Q9HCE5) and WTAP (UniProtKB:Q15007), but additional component subunits have recently been identified (18).”
• The role of m6A RNA methylation in cancer metabolism (2022, background): “Among them, KIAA1429, as the largest scaffold component of m6A methyltransferase complex, is used to regulate 3’-UTR of genes and m6A methylation near the stop codon [23, 24].”
• Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “recently reported that VIRMA/KIAA1429 recruits the catalytic core components (METTL3/METTL14/WTAP) to guide region-selective m(6)A methylation.(81)”
• Functions of N6-methyladenosine and its role in cancer (2019, background): “VIRMA recruits the m6A complex to the special RNA site and interacts with polyadenylation cleavage factors CPSF5 and CPSF6 [18]”
• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “, 2008); Vir like m6A methyltransferase associated (VIRMA) is critical for deposition of m6A specifically to the 3’UTR (Yue et al., 2018); Zinc finger CCCH-type containing 13 (ZC3H13) facilitates nuclear localization of the writer complex (Wen et al.”
• m6A RNA methylation: from mechanisms to therapeutic potential (2021, neutral): “:3) u (cid:4) zi (cid:4) cka et al , 2017; Guo et al , 2018; ; Wen et al , 2018; Yue et al , 2018).”
• The potential role of RNA N6-methyladenosine in Cancer progression (2020, background): “Virlike m6A methyltransferase associated (VIRMA/ KIAA1429) preemptively recruits the MTC and mediates methylation of adenine bases near the 3′ UTR and stop codon regions in mRNA; it also interacts with cleavage and polyadenylation specificity factor subunit 5 (CPSF5) and cleavage and polyadenylation”
• Methylation multiplicity and its clinical values in cancer (2021, neutral): “24), and zinc finger CCCH-type containing 13 that could promote the nucleus localisation of the core complex (Ref.”