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2015 ; 519
(7544
): 482-5
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N6-methyladenosine marks primary microRNAs for processing
#MMPMID25799998
Alarcón CR
; Lee H
; Goodarzi H
; Halberg N
; Tavazoie SF
Nature
2015[Mar]; 519
(7544
): 482-5
PMID25799998
show ga
The first step in the biogenesis of microRNAs is the processing of primary
microRNAs (pri-miRNAs) by the microprocessor complex, composed of the RNA-binding
protein DGCR8 and the type III RNase DROSHA. This initial event requires
recognition of the junction between the stem and the flanking single-stranded RNA
of the pri-miRNA hairpin by DGCR8 followed by recruitment of DROSHA, which
cleaves the RNA duplex to yield the pre-miRNA product. While the mechanisms
underlying pri-miRNA processing have been determined, the mechanism by which
DGCR8 recognizes and binds pri-miRNAs, as opposed to other secondary structures
present in transcripts, is not understood. Here we find in mammalian cells that
methyltransferase-like 3 (METTL3) methylates pri-miRNAs, marking them for
recognition and processing by DGCR8. Consistent with this, METTL3 depletion
reduced the binding of DGCR8 to pri-miRNAs and resulted in the global reduction
of mature miRNAs and concomitant accumulation of unprocessed pri-miRNAs. In vitro
processing reactions confirmed the sufficiency of the N(6)-methyladenosine
(m(6)A) mark in promoting pri-miRNA processing. Finally, gain-of-function
experiments revealed that METTL3 is sufficient to enhance miRNA maturation in a
global and non-cell-type-specific manner. Our findings reveal that the m(6)A mark
acts as a key post-transcriptional modification that promotes the initiation of
miRNA biogenesis.
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