2025/08/21 by Akiko Ogawa, Satoshi Watanabe, Iuliia Ozerova +20 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Adenosine and Purinergic Signaling #RNA modifications and cancer #Biochemical and Molecular Research
paper · pdf · doi:10.1016/j.cell.2025.07.041
openalex publication_date 2025/08/21 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/22
RNA contains diverse post-transcriptional modifications, and its catabolic breakdown yields numerous modified nucleosides requiring correct processing, but the mechanisms remain unknown. Here, we demonstrate that three RNA-derived modified adenosines, N 6 -methyladenosine (m 6 A), N 6 , N 6 -dimethyladenosine (m 6,6 A), and N 6 -isopentenyladenosine (i 6 A), are sequentially metabolized into inosine monophosphate (IMP) to mitigate their intrinsic cytotoxicity. After phosphorylation by adenosine kinase (ADK), they undergo deamination by adenosine deaminase-like (ADAL). In Adal knockout mice, N 6 -modified adenosine monophosphates (AMPs) accumulate and allosterically inhibit AMP-activated protein kinase (AMPK), dysregulating glucose metabolism. Furthermore, ADK deficiency, linked to human inherited disorders of purine metabolism, elevates levels of the three modified adenosines, resulting in early lethality in mice. Mechanistically, excessive m 6 A, m 6,6 A, and i 6 A impair lysosomal function by interfering with lysosomal membrane proteins, thereby disrupting lipid metabolism and causing cellular toxicity. Through this nucleotide metabolism pathway and mechanism, cells detoxify modified adenosines, linking modified RNA metabolism to human disease.