ALKBH3 partner ASCC3 mediates P-body formation and selective clearance of MMS-induced 1-methyladenosine and 3-methylcytosine from mRNA
| Autor: | Per Arne Aas, Renana Rabe, Vuk Palibrk, Geir Slupphaug, Kristian Lied Wollen, Lars Hagen, Davi de Miranda Fonseca, Hilde O. Erlandsen, Animesh Sharma, Cathrine Broberg Vågbø, Tobias S. Iveland, Magnar Bjørås, Bjørnar Sporsheim, Nima Mosammaparast |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Adenosine
Ubiquitin-Protein Ligases 7-Methylguanosine Ribosome Alkylating agents General Biochemistry Genetics and Molecular Biology ASCC3 Tripartite Motif Proteins 03 medical and health sciences Cytosine 0302 clinical medicine Ribosomal protein Ribosome quality control P-bodies Animals Humans Eukaryotic Small Ribosomal Subunit RNA Messenger 030304 developmental biology 0303 health sciences Messenger RNA ALKBH3 biology Chemistry Research 3-Methylcytosine DNA Helicases RNA Epitranscriptome General Medicine Methylation Cell biology biology.protein Demethylase Medicine 1-Methyladenosine No-go decay AlkB Homolog 3 Alpha-Ketoglutarate-Dependent Dioxygenase Ribosomes 030217 neurology & neurosurgery RNA Helicases Transcription Factors |
| Zdroj: | Journal of Translational Medicine Journal of Translational Medicine, Vol 19, Iss 1, Pp 1-22 (2021) |
| ISSN: | 1479-5876 |
| Popis: | Background Reversible enzymatic methylation of mammalian mRNA is widespread and serves crucial regulatory functions, but little is known to what degree chemical alkylators mediate overlapping modifications and whether cells distinguish aberrant from canonical methylations. Methods Here we use quantitative mass spectrometry to determine the fate of chemically induced methylbases in the mRNA of human cells. Concomitant alteration in the mRNA binding proteome was analyzed by SILAC mass spectrometry. Results MMS induced prominent direct mRNA methylations that were chemically identical to endogenous methylbases. Transient loss of 40S ribosomal proteins from isolated mRNA suggests that aberrant methylbases mediate arrested translational initiation and potentially also no-go decay of the affected mRNA. Four proteins (ASCC3, YTHDC2, TRIM25 and GEMIN5) displayed increased mRNA binding after MMS treatment. ASCC3 is a binding partner of the DNA/RNA demethylase ALKBH3 and was recently shown to promote disassembly of collided ribosomes as part of the ribosome quality control (RQC) trigger complex. We find that ASCC3-deficient cells display delayed removal of MMS-induced 1-methyladenosine (m1A) and 3-methylcytosine (m3C) from mRNA and impaired formation of MMS-induced P-bodies. Conclusions Our findings conform to a model in which ASCC3-mediated disassembly of collided ribosomes allows demethylation of aberrant m1A and m3C by ALKBH3. Our findings constitute first evidence of selective sanitation of aberrant mRNA methylbases over their endogenous counterparts and warrant further studies on RNA-mediated effects of chemical alkylators commonly used in the clinic. |
| Databáze: | OpenAIRE |
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