Diadenosine Tetraphosphate (Ap4 A) Serves as a 5' RNA Cap in Mammalian Cells
Jazyk angličtina Země Německo Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
101041374
HORIZON EUROPE European Research Council
PubMed
37934413
DOI
10.1002/anie.202314951
Knihovny.cz E-zdroje
- Klíčová slova
- Ap4A, Ap4A-RNA, Diadenosine Tetraphosphate, RNA Cap, RNA Modification,
- MeSH
- dinukleosidfosfáty * metabolismus MeSH
- fosfatasy MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- NUDIX hydrolasy MeSH
- RNA čepičky * MeSH
- savci metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- diadenosine tetraphosphate MeSH Prohlížeč
- dinukleosidfosfáty * MeSH
- fosfatasy MeSH
- NUDIX hydrolasy MeSH
- NUDT2 protein, human MeSH Prohlížeč
- RNA čepičky * MeSH
The recent expansion of the field of RNA chemical modifications has changed our understanding of post-transcriptional gene regulation. Apart from internal nucleobase modifications, 7-methylguanosine was long thought to be the only eukaryotic RNA cap. However, the discovery of non-canonical RNA caps in eukaryotes revealed a new niche of previously undetected RNA chemical modifications. We are the first to report the existence of a new non-canonical RNA cap, diadenosine tetraphosphate (Ap4 A), in human and rat cell lines. Ap4 A is the most abundant dinucleoside polyphosphate in eukaryotic cells and can be incorporated into RNA by RNA polymerases as a non-canonical initiating nucleotide (NCIN). Using liquid chromatography-mass spectrometry (LC-MS), we show that the amount of capped Ap4 A-RNA is independent of the cellular concentration of Ap4 A. A decapping enzyme screen identifies two enzymes cleaving Ap4 A-RNA,NUDT2 and DXO, both of which also cleave other substrate RNAs in vitro. We further assess the translatability and immunogenicity of Ap4 A-RNA and show that although it is not translated, Ap4 A-RNA is recognized as self by the cell and does not elicit an immune response, making it a natural component of the transcriptome. Our findings open a previously unexplored area of eukaryotic RNA regulation.
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