Base editors (BEs) are double-strand break (DSB)-free genome editing agents that install point mutations with high efficiency and specificity. Because of their reliance on uracil and inosine DNA damage intermediates, it has been hypothesized that BEs are more ubiquitous than precision DSB-reliant genome editing methods, which require DNA repair processes that are only active during certain phases of the cell cycle. I will describe in my talk the first systematic study of the cell cycle-dependence of base editing via cell synchronization experiments. These experimends reveal that nickase-derived BEs (which introduce DNA backbone nicks opposite the uracil or inosine base) function independently of the cell cycle, while non-nicking BEs are highly dependent on cell cycle status. Additionally, I will describe our analysis of the cell cycle-dependence of DNA damage repair genes in single-cell RNAseq datasets. A comparison of these analyses with our synchronization data suggests that nickase-derived BEs rely on the long-patch base excision repair pathway to install point mutations.

Investigations of the cellular mechanisms of base editing

ACS Fall 2021

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