YTHDF2 Recognition of N1-Methyladenosine (m1A)-Modified RNA Is Associated with Transcript Destabilization.

TitleYTHDF2 Recognition of N1-Methyladenosine (m1A)-Modified RNA Is Associated with Transcript Destabilization.
Publication TypeJournal Article
Year of Publication2020
AuthorsSeo, KW, Kleiner, RE
JournalACS Chem Biol
Volume15
Issue1
Pagination132-139
Date Published2020 Jan 17
ISSN1554-8937
Abstract

Epitranscriptomic modifications play an important role in RNA function and can impact gene expression. Here, we apply a chemical proteomics approach to investigate readers of N1-methyladenosine (m1A), a poorly characterized modification on mammalian mRNA. We find that YTHDF proteins, known m6A readers, recognize m1A-modified sequences in a methylation-specific manner. We characterize binding of recombinant YTHDF1/2 proteins to m1A-modified oligonucleotides to demonstrate that these interactions can exhibit comparable affinity to m6A-recognition events and occur in diverse sequence contexts. Further, we demonstrate YTHDF2 interacts specifically with endogenously modified m1A transcripts. Finally, we deplete cellular YTHDF2 to show that the abundance of m1A-modified transcripts is increased in its absence. Similarly, increasing m1A levels through depletion of ALKBH3, an m1A eraser protein, destabilizes known m1A-containing RNAs. Our results shed light on the function of m1A on mRNA and provide a mechanistic framework to further evaluate the role of m1A in biological processes.

DOI10.1021/acschembio.9b00655
Alternate JournalACS Chem. Biol.
PubMed ID31815430