APE1 distinguishes DNA substrates in exonucleolytic cleavage by induced space-filling

Tung Chang Liu, Chun Ting Lin, Kai Cheng Chang, Kai Wei Guo, Shuying Wang, Jhih-Wei Chu, Yu-Yuan Hsiao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The exonuclease activity of Apurinic/apyrimidinic endonuclease 1 (APE1) is responsible for processing matched/mismatched terminus in various DNA repair pathways and for removing nucleoside analogs associated with drug resistance. To fill in the gap of structural basis for exonucleolytic cleavage, we determine the APE1-dsDNA complex structures displaying end-binding. As an exonuclease, APE1 does not show base preference but can distinguish dsDNAs with different structural features. Integration with assaying enzyme activity and binding affinity for a variety of substrates reveals for the first time that both endonucleolytic and exonucleolytic cleavage can be understood by an induced space-filling model. Binding dsDNA induces RM (Arg176 and Met269) bridge that defines a long and narrow product pocket for exquisite machinery of substrate selection. Our study paves the way to comprehend end-processing of dsDNA in the cell and the drug resistance relating to APE1.

Original languageEnglish
Article number601
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - 27 Jan 2021

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