Adenosine deaminase acting on RNA 1 Z-alpha domain (ADAR1 Zα domain) (ADAR1 Zα)

The Adenosine deaminase acting on RNA 1 (ADAR1) Z-alpha (Zα) domain is a specialized nucleic acid-binding motif found in the interferon-inducible p150 isoform of the ADAR1 enzyme (UniProt P55265). This domain is unique for its high-affinity binding to left-handed Z-DNA and Z-RNA, which are high-energy conformations of double-stranded nucleic acids (Herbert, 2019). Biologically, the Zα domain targets ADAR1 to specific double-stranded RNA (dsRNA) substrates, such as Alu elements, where the enzyme performs adenosine-to-inosine (A-to-I) editing (Fritzell et al., 2019). This editing process is essential for distinguishing self RNA from viral RNA, as it prevents the activation of the MDA5-mediated innate immune pathway by endogenous transcripts (Mao et al., 2022). In many cancers, ADAR1 is upregulated to suppress the sensing of immunogenic dsRNA, thereby promoting immune evasion and resistance to checkpoint inhibitors (Ishizuka et al., 2019). Consequently, the Zα domain is a high-interest therapeutic target for small molecule inhibitors designed to unmask tumor RNA and stimulate a robust anti-tumor immune response (Gannon et al., 2018). However, therapeutic intervention must be carefully managed, as genetic defects in this domain are known to cause Aicardi-Goutières Syndrome, a severe autoinflammatory disease (Rice et al., 2012).

Other names

ADAR1 Z-alpha domainZ-DNA binding domain of ADAR1DSRADIFI4K88DSRBPp150 ADAR1

Inhibition of the Z-alpha domain prevents ADAR1 from binding to and editing Z-RNA, leading to the accumulation of immunogenic double-stranded RNA and subsequent activation of the MDA5-mediated innate immune response (Ishizuka et al., 2019).