Excel · study · 2026
5-Azacytidine incorporation into mRNAs disrupts translation and induces ribosome collisions
Listed in NCBI GEO
5-Azacytidine (5-AzaC) is a cytidine analog and is widely used to treat myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
Description
Although its therapeutic activity is primarily attributed to hypomethylation resulting from DNA incorporation, the majority of 5-AzaC is incorporated into RNA. However, the functional consequences of 5-AzaC incorporation into RNAs have been unknown.
Here, we show that 5-AzaC treatment of cells leads to inhibition of protein synthesis. Ribo-seq, Disome-seq, and RNA-seq in cells treated with 5-AzaC show a time-dependent C-to-G transversion signature in mRNAs within 2 h of treatment. These transversion events are enriched within footprints at positions corresponding to the A-site of the monosome or leading stalled ribosome in a disome complex.
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Consistently, ribosome and disome footprints are enriched at sites with C-rich codons in the A-site, specifically with the codons containing a C in the second position. Disome formation induced by 5-AzaC activates the integrated stress response (ISR) through phosphorylation of eIF2α by GCN2 and the ribotoxic stress response (RSR) through phosphorylation of p38 and JNK by ZAK. Furthermore, loss of Ribosome Quality Control (RQC) factor, ZNF598 sensitizes cells to 5-AzaC.
Collectively, our results support a model where 5-AzaC is rapidly incorporated into mRNAs, disrupts decoding, and triggers disome-mediated signaling pathways, which contribute to its cytotoxicity. These findings suggest that translation disruption represents an additional layer of 5-AzaC’s mechanism of action, alongside its known DNA-mediated effects.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE326nnn/GSE326239 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE326239 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1444183 ncbi.nlm.nih.gov/bioproject/PRJNA1444183 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens · Other
- From keywords
- Life Sciences
- Inferred from text
- RNA sequencing 65%
Provenance · 1 source records, 9 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE326239 | 14 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[method].geo_series_type:other | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |