NAT10 and N4-acetylcytidine restrain R-loop levels and related inflammatory responses
N4-acetylcytidine (ac4C) is deposited on diverse RNAs by N-acetyltransferase 10 (NAT10), a protein with high biological relevance for aging and cancer. We performed a comprehensive survey of ac4C using metabolic labeling, sodium cyanoborohydride chemical treatment coupled to next-generation sequenci...
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| Vydáno v: | Science advances Ročník 11; číslo 13; s. eads6144 |
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| Hlavní autoři: | , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
American Association for the Advancement of Science
26.03.2025
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| Témata: | |
| ISSN: | 2375-2548, 2375-2548 |
| On-line přístup: | Získat plný text |
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| Shrnutí: | N4-acetylcytidine (ac4C) is deposited on diverse RNAs by N-acetyltransferase 10 (NAT10), a protein with high biological relevance for aging and cancer. We performed a comprehensive survey of ac4C using metabolic labeling, sodium cyanoborohydride chemical treatment coupled to next-generation sequencing (NGS), and ac4C antibody-based cell and molecular biology techniques. Our analysis shows that NAT10-dependent ac4C-acetylation is robust in rRNA and specific tRNAs but low/spurious in mRNA. It also revealed an inflammatory signature and mutagenesis at transcriptionally active sites in NAT10-KO cells. This finding led us to explore the role of NAT10 in R-loops, which were recently linked to APOBEC3B-mediated mutagenesis. Our analysis showed that R-loops are ac4C-acetylated in a NAT10-dependent manner. Furthermore, NAT10 restrains the levels of R-loops at a subset of differentially expressed genes in a catalytic activity-dependent manner. Together with cellular biology data showing ac4C-modified RNA in endosomal structures, we propose that increased levels of ac4C-unmodified RNAs, likely derived from R-loops, in endosomal structures induce inflammatory responses.N4-acetylcytidine (ac4C) is deposited on diverse RNAs by N-acetyltransferase 10 (NAT10), a protein with high biological relevance for aging and cancer. We performed a comprehensive survey of ac4C using metabolic labeling, sodium cyanoborohydride chemical treatment coupled to next-generation sequencing (NGS), and ac4C antibody-based cell and molecular biology techniques. Our analysis shows that NAT10-dependent ac4C-acetylation is robust in rRNA and specific tRNAs but low/spurious in mRNA. It also revealed an inflammatory signature and mutagenesis at transcriptionally active sites in NAT10-KO cells. This finding led us to explore the role of NAT10 in R-loops, which were recently linked to APOBEC3B-mediated mutagenesis. Our analysis showed that R-loops are ac4C-acetylated in a NAT10-dependent manner. Furthermore, NAT10 restrains the levels of R-loops at a subset of differentially expressed genes in a catalytic activity-dependent manner. Together with cellular biology data showing ac4C-modified RNA in endosomal structures, we propose that increased levels of ac4C-unmodified RNAs, likely derived from R-loops, in endosomal structures induce inflammatory responses. |
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| Bibliografie: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. |
| ISSN: | 2375-2548 2375-2548 |
| DOI: | 10.1126/sciadv.ads6144 |