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

Autor: Liu TC; Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, 30068, Taiwan.; Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan., Lin CT; Master's and Doctoral Degree Program for Science and Technology of Accelerator Light Sources, National Chiao Tung University, Hsinchu, 30068, Taiwan., Chang KC; Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan., Guo KW; Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan., Wang S; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.; Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan., Chu JW; Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, 30068, Taiwan.; Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan.; Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, 30068, Taiwan.; Center For Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Chiao Tung University, Hsinchu, Taiwan., Hsiao YY; Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, 30068, Taiwan. mike0617@nctu.edu.tw.; Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan. mike0617@nctu.edu.tw.; Master's and Doctoral Degree Program for Science and Technology of Accelerator Light Sources, National Chiao Tung University, Hsinchu, 30068, Taiwan. mike0617@nctu.edu.tw.; Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, 30068, Taiwan. mike0617@nctu.edu.tw.; Center For Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Chiao Tung University, Hsinchu, Taiwan. mike0617@nctu.edu.tw.; Drug Development and Value Creation Research Center, Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan. mike0617@nctu.edu.tw.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Jan 27; Vol. 12 (1), pp. 601. Date of Electronic Publication: 2021 Jan 27.
DOI: 10.1038/s41467-020-20853-2
Abstrakt: 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.
Databáze: MEDLINE