The comprehensive interactomes of human adenosine RNA methyltransferases and demethylases reveal distinct functional and regulatory features

• Published in: Nucleic acids research 2021-11, Vol.49 (19), p.10895-10910
• Main Authors: Covelo-Molares, Helena, Obrdlik, Ales, Poštulková, Ivana, Dohnálková, Michaela, Gregorová, Pavlína, Ganji, Ranjani, Potěšil, David, Gawriyski, Lisa, Varjosalo, Markku, Vaňáčová, Štěpánka
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adenosine - analogs & derivatives; Adenosine - metabolism; AlkB Homolog 5, RNA Demethylase - genetics; AlkB Homolog 5, RNA Demethylase - metabolism; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - metabolism; Data Resources and Analyses; DNA Repair; DNA Replication; Gene Ontology; HEK293 Cells; Humans; Methyltransferases - genetics; Methyltransferases - metabolism; Molecular Sequence Annotation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oxidoreductases, N-Demethylating - genetics; Oxidoreductases, N-Demethylating - metabolism; Protein Binding; Protein Interaction Mapping; Protein Isoforms - genetics; Protein Isoforms - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Untranslated - genetics; RNA, Untranslated - metabolism; Transcription, Genetic
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkab900

Abstract N6-methyladenosine (m6A) and N6,2′-O-dimethyladenosine (m6Am) are two abundant modifications found in mRNAs and ncRNAs that can regulate multiple aspects of RNA biology. They function mainly by regulating interactions with specific RNA-binding proteins. Both modifications are linked to development, disease and stress response. To date, three methyltransferases and two demethylases have been identified that modify adenosines in mammalian mRNAs. Here, we present a comprehensive analysis of the interactomes of these enzymes. PCIF1 protein network comprises mostly factors involved in nascent RNA synthesis by RNA polymerase II, whereas ALKBH5 is closely linked with most aspects of pre-mRNA processing and mRNA export to the cytoplasm. METTL16 resides in subcellular compartments co-inhabited by several other RNA modifiers and processing factors. FTO interactome positions this demethylase at a crossroad between RNA transcription, RNA processing and DNA replication and repair. Altogether, these enzymes share limited spatial interactomes, pointing to specific molecular mechanisms of their regulation.