Cap-specific terminal N ⁶ -methylation of RNA by an RNA polymerase II–associated methyltransferase

Abstract

N6-methyladenosine (m6A), a major modification of messenger RNAs (mRNAs), plays critical roles in RNA metabolism and function. In addition to the internal m6A, N6, 2′-O-dimethyladenosine (m6Am) is present at the transcription start nucleotide of capped mRNAs in vertebrates. However, its biogenesis and functional role remain elusive. Using a reverse genetics approach, we identified PCIF1, a factor that interacts with the serine-5–phosphorylated carboxyl-terminal domain of RNA polymerase II, as a cap-specific adenosine methyltransferase (CAPAM) responsible for N6-methylation of m6Am. The crystal structure of CAPAM in complex with substrates revealed the molecular basis of cap-specific m6A formation. A transcriptome-wide analysis revealed that N6-methylation of m6Am promotes the translation of capped mRNAs. Thus, a cap-specific m6A writer promotes translation of mRNAs starting from m6Am.

Codon bias confers stability to humanmRNAs

“…Reads were aligned to human hg38 genome as described [34,88]. Reads were aligned to human hg38 genome as described [34,88].…”

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

“…It is worth noting that this study demonstrates that overexpression of miR‐24‐2 in human hepatoma cell line Hep3B promotes the expression of N6‐adenine methyltransferase METTL3 and thereby increases methylation modification (m6A) on N6‐adenosine from specific RNA. Indeed, m6A is one of the major modifications of RNA that regulates the processing, translation and decay of RNA, which plays a key role in RNA metabolism and function . Furthermore, m6A, which is mainly catalysed by METTL3, regulates RNA stability mainly through m6A‐specific binding proteins which in turn determines cellular fate and function .…”

Combining Chemical Synthesis and Enzymatic Methylation to Access Short RNAs with Various 5′ Caps

“…The formation of cap1 and cap2 structures in humans is catalyzed by cap methyltransferases 1 and 2 (CMTR1 and CMTR2), respectively . In contrast to previous results, recent findings suggest that 2′‐O‐methylation is constitutive, but its precise function remains to be elucidated . Although 2′‐O‐methylation was shown to have an enhancing effect on ribosome binding and translation, Bélanger et al.…”

“…As recently discovered, further modifications can include methylation at the N 6 ‐position if the first transcribed nucleotide is an adenosine in mRNAs and snRNAs. This modification occurs only on 2′‐O‐methylated RNAs, yielding 6m A m , and is theorized to happen co‐transcriptionally upon cap1 formation and to influence mRNA stability . In snRNAs, recent findings suggest that methylation at the N 6 ‐position of the first 2′‐O‐methyl adenosine is dynamic; thus indicating a regulatory function of 6m A m in splicing or other snRNA‐dependent mRNA processing reactions …”