Bystander adenines within the on-target editing window

Bystander adenines within the on-target editing window refer to adenine bases located near a target nucleotide that are unintentionally modified during base editing (Gaudelli et al., 2017). In Adenine Base Editing (ABE), a CRISPR-Cas9 system is fused to a deaminase enzyme like TadA to convert A-T base pairs to G-C base pairs (Richter et al., 2020). The deaminase operates within a specific window, typically 4 to 8 nucleotides wide, and any adenine within this range is susceptible to deamination (Kim et al., 2019). This phenomenon, known as bystander editing, can lead to unintended missense mutations or alterations in regulatory sequences, posing a significant safety concern for clinical applications (Koblan et al., 2018). While not a therapeutic target in the traditional sense, these adenines represent a critical technical liability that researchers aim to minimize through the engineering of high-fidelity deaminases or narrowed editing windows (Rees & Liu, 2018). Understanding and predicting bystander editing is essential for the design of precise gene therapies for genetic disorders like sickle cell disease or progeria (Musunuru, 2020).

Other names

Bystander adeninesBystander basesProximal adeninesOff-target adenines within the activity window

Hydrolytic deamination of adenine to inosine by deoxyadenosine deaminases, which is subsequently paired with cytosine during DNA replication, resulting in an A-to-G transition.