Publications

• m6A RNA degradation products are catabolized by an evolutionarily conserved N6-methyl-AMP deaminase in plant and mammalian cells.

  Chen M., Urs M.J., Sanchez-Gonzalez I., Olayioye M.A., Herde M., Witte C.P.

  N⁶-methylated adenine (m⁶A) is the most frequent posttranscriptional modification in eukaryotic mRNA. Turnover of RNA generates N⁶-methylated AMP (N⁶-mAMP), which has an unclear metabolic fate. We show that <i>Arabidopsis thaliana</i> and human cells req ... >> More

  N⁶-methylated adenine (m⁶A) is the most frequent posttranscriptional modification in eukaryotic mRNA. Turnover of RNA generates N⁶-methylated AMP (N⁶-mAMP), which has an unclear metabolic fate. We show that <i>Arabidopsis thaliana</i> and human cells require an N⁶-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N⁶-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group. A phylogenetic, structural, and biochemical analysis revealed that many fungi partially or fully lack MAPDA, which coincides with a minor role of N⁶A-RNA methylation in these organisms. MAPDA likely protects RNA from m⁶A misincorporation. This is required because eukaryotic RNA polymerase can use N⁶-mATP as a substrate. Upon abrogation of <i>MAPDA</i>, root growth is slightly reduced, and the N⁶-methyladenosine, N⁶-mAMP, and N⁶-mATP concentrations are increased in Arabidopsis. Although this will potentially lead to m⁶A misincorporation into RNA, we show that the frequency is too low to be reliably detected in vivo. Since N⁶-mAMP was severalfold more abundant than N⁶-mATP in <i>MAPDA</i> mutants, we speculate that additional molecular filters suppress the generation of N⁶-mATP. Enzyme kinetic data indicate that adenylate kinases represent such filters being highly selective for AMP versus N⁶-mAMP phosphorylation. We conclude that a multilayer molecular protection system is in place preventing N⁶-mAMP accumulation and salvage. << Less

  Plant Cell 30:1511-1522(2018) [PubMed] [EuropePMC]

• Adenosine kinase and ADAL coordinate detoxification of modified adenosines to safeguard metabolism.

  Ogawa A., Watanabe S., Ozerova I., Tsai A.Y., Kuchitsu Y., Chong H.B., Kawakami T., Fuse J., Han W., Kudo R., Naito T., Sato K., Nakazawa T., Saheki Y., Hirayama A., Stadler P.F., Arisawa M., Araki K., Bar-Peled L., Taguchi T., Sawa S., Inaba K., Wei F.Y.

  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, N⁶-methyladenosine (m⁶A) ... >> More

  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, N⁶-methyladenosine (m⁶A), N⁶,N⁶-dimethyladenosine (m^6,6A), and N⁶-isopentenyladenosine (i⁶A), 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, N⁶-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 m⁶A, m^6,6A, and i⁶A 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. << Less

  Cell 0:0-0(2025) [PubMed] [EuropePMC]

  This publication is cited by 6 other entries.