The deaminase ADAL-pivoted catabolism checkpoint suppresses aberrant DNA N6-methyladenine incorporation

Abstract

Abundant RNA N6-methyladenine (m6A) is degraded in RNA decay and potentially induces aberrant DNA N6-methyladenine (6mA) misincorporation. Biophysically, like truly methylated product DNA 6mA, misincorporated 6mA also destabilizes the DNA double helix and thus ditto affects DNA replication and transcription. By heavy stable isotope tracing, we demonstrate that intracellular degradation of RNA m6A cannot induce any misincorporated DNA 6mA, unveiling the existence of a catabolism checkpoint that blocks DNA 6mA misincorporation. We further show that the deaminase ADAL preferentially catabolizes N6-methyl-2’-deoxyadenosine monophosphate (6mdAMP) in vitro and in vivo, and adenylate kinase 1 restricts the phosphorylation rate of 6mdAMP, together contributing to the identified checkpoint. Noteworthy, low ADAL expression reduces dramatically the patient survival in four cancers. Collectively, our data strongly support a pivotal role of ADAL in the suppression of 6mA misincorporation and implicate that both ADAL and misincorporated 6mA may mark cancer abnormalities.