Harnessing nucleotide metabolism to control glycosylase base editing outcomes.

ABSTRACT:

Rationale

Glycosylase-derived base editors enable transversion base substitutions, expanding the scope of genome engineering for both basic research and clinical applications. However, the variable outcomes and low efficiency of B (C/G/T)-to-A editing in mammalian cells hinder their broader utility, likely due to inefficient thymine translesion synthesis (TLS) across apurinic/apyrimidinic (AP) sites.

Methods and results

We developed a nucleotide metabolism-based strategy to enhance B-to-A editing by leveraging endogenous nucleotide metabolism. We showed that elevating intracellular deoxythymidine triphosphate (dTTP) levels via exogenous thymidine (dT) supplementation, which activates the thymidine kinase 1 (TK1)-dependent salvage pathway for the production of dTTP, increased

SUBMITTER: Tao R 

PROVIDER: S-EPMC12906143 | biostudies-literature | 2026

REPOSITORIES: biostudies-literature