Abstract
N6-methyladenosine (m6A) is the most abundant internal modification of eukaryotic mRNA. This modification has previously been shown to alter the export kinetics for mRNAs though the molecular details surrounding this phenomenon remain poorly understood. Recruitment of the TREX mRNA export complex to mRNA is driven by transcription, 5′ capping and pre-mRNA splicing. Here we identify a fourth mechanism in human cells driving the association of TREX with mRNA involving the m6A methylase complex. We show that the m6A complex recruits TREX to m6A modified mRNAs and this process is essential for their efficient export. TREX also stimulates recruitment of the m6A reader protein YTHDC1 to the mRNA and the m6A complex influences the interaction of TREX with YTHDC1. Together our studies reveal a key role for TREX in the export of m6A modified mRNAs.
Highlights
The transport of mRNA from the nucleus to the cytoplasm represents a key step in the eukaryotic gene expression pathway. mRNA export is closely coupled with capping, splicing and 3′ end processing of primary transcripts[1]
Together these results indicate that TREX associates with the m6A methylase complex
Consistent with YTHDC1 acting downstream of ALYREF in mRNA export, we observed a significant increase in the amounts of mRNAs subject to m6A modification associated with ALYREF following knockdown of YTHDC1, rather than a decrease
Summary
The transport of mRNA from the nucleus to the cytoplasm represents a key step in the eukaryotic gene expression pathway. mRNA export is closely coupled with capping, splicing and 3′ end processing of primary transcripts[1]. TREX triggers the recruitment of the NXF1:NXT1 heterodimer which is required for translocation of mRNA from its site of transcription through the nuclear pore to the cytoplasm. RBM15 and RBM15B bind the methylase complex and recruit it to specific sites in mRNA16 Both RBM15 and RBM15B have been implicated in mRNA export control[17,18]. Evidence of a connection between mRNA export and m6A comes from a class of proteins known as “erasers” (ALKBH5 and FTO) that can remove the modification Both are members of the same ALKB subfamily of Fe(II)/2-oxoglutarate dioxygenases. ALKBH5 is located in nuclear speckles in common with mRNA splicing and export factors and its loss is reported to lead to increased cytoplasmic poly(A)+ RNA signal, suggesting an alteration in mRNA export control though again the molecular mechanisms involved are unclear[31]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
