ADAR1 as an epitranscriptomic arbiter and genome guardian: rewiring gene expression through the A-to-I editome

ADAR1 catalyzes the conversion of adenosine to inosine in double-stranded RNA (dsRNA) substrates, providing a biological means to regulate cellular responses via gene expression rewiring. This review will highlight the primary functions of ADAR1 and describe how the combination of these functions—primarily epitranscriptomic, with emerging links to chromatin and DNA repair—provides ADAR1 with the ability to influence the genetic stability of cell. ADAR1 has four primary functions; (1) ADAR1 alters the biogenesis of microRNA and competing endogenous RNA networks, thus reshaping the regulatory environment of the cell with respect to non-coding RNAs; (2) ADAR1 collaborates with chromatin to promote DNA demethylation through the actions of TET proteins and cooperates with the N6-methyladenosine RNA modification; (3) ADAR1 facilitates DNA damage repair by resolving R-loops, which can otherwise impede repair, and contributes to maintaining telomere stability; and (4) ADAR1 serves as a transcriptional co-regulator and provides a scaffold for maintaining and differentiating stem cells, where it is required for its editing function. This refreshed understanding of ADAR1 as a prominent epigenetic regulator was not previously appreciated to be so broad; future therapeutic strategies are anticipated to target modifying chemistry and altering how ADAR1 regulates the cell during cancer and disease.