Genomic DNA adenine bases at the intended editing locus

Genomic DNA adenine bases at the intended editing locus serve as the specific chemical substrate for Adenine Base Editors (ABEs). These therapeutic systems typically employ a CRISPR-Cas9 nickase (nCas9) tethered to an evolved TadA (tRNA-specific adenosine deaminase) enzyme (Gaudelli et al., Nature, 2017). Guided by a specific single-guide RNA (sgRNA), the complex binds to a complementary DNA sequence, where the deaminase converts a specific adenine into inosine. Because inosine is interpreted as guanine by cellular machinery during DNA replication or repair, the process effectively achieves a precise A-T to G-C point mutation without inducing double-strand breaks (Beam Therapeutics, 2024). This target is central to treating genetic diseases caused by G-to-A mutations, such as sickle cell disease and alpha-1 antitrypsin deficiency, where editing can restore normal protein function or modulate gene expression (Kantor et al., 2020). By avoiding double-strand breaks, targeting these adenine bases reduces the risk of unintended insertions, deletions, or chromosomal translocations compared to traditional CRISPR-Cas9 methods.

Other names

Target adenineAdenosine in genomic DNATarget A-T base pairGenomic adenine substrate

The mechanism involves the hydrolytic deamination of the target adenine base to inosine by a deoxyadenosine deaminase (e.g., evolved TadA). Inosine is subsequently read as guanine by DNA polymerase during DNA replication or through the mismatch repair pathway, resulting in a permanent A-T to G-C transition (Gaudelli et al., Nature, 2017).