Protein Domain Specific Covalent Inhibition of Human DNA Polymerase β

DNA polymerase β (Pol β) is a frequently overexpressed and/or mutated bifunctional repair enzyme. Pol β possesses polymerase and lyase active sites, that are employed in two steps of base excision repair. Pol β is an attractive therapeutic target for which there is a need for inhibitors. Two mechani...

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Bibliographic Details
Published in:Chembiochem : a European journal of chemical biology 2021-08, Vol.22 (16), p.2619-2623
Main Authors: Yuhas, Shelby C., Majumdar, Ananya, Greenberg, Marc M.
Format: Article
Language:English
Subjects:
Anisotropy
Base excision repair
Catalytic Domain
Communication
Communications
covalent inhibitors
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA - metabolism
DNA damage
DNA polymerase
DNA Polymerase beta - antagonists & inhibitors
DNA Polymerase beta - chemistry
DNA Polymerase beta - metabolism
DNA polymerases
DNA repair
DNA-directed DNA polymerase
enzyme inhibition
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Fluorescence
Fluorescence Polarization
Humans
Inhibitors
Lysine
Protein Domains
Repair
Residues
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Summary:DNA polymerase β (Pol β) is a frequently overexpressed and/or mutated bifunctional repair enzyme. Pol β possesses polymerase and lyase active sites, that are employed in two steps of base excision repair. Pol β is an attractive therapeutic target for which there is a need for inhibitors. Two mechanistically inspired covalent inhibitors (1, IC50=21.0 μM; 9, IC50=18.7 μM) that modify lysine residues in different Pol β active sites are characterized. Despite modifying lysine residues in different active sites, 1 and 9 inactivate the polymerase and lyase activities of Pol β. Fluorescence anisotropy experiments indicate that they do so by preventing DNA binding. Inhibitors 1 and 9 provide the basis for a general approach to preparing domain selective inhibitors of bifunctional polymerases. Such molecules could prove to be useful tools for studying the role of wild type and mutant forms of Pol β and other polymerases in DNA repair. A single synthesis and screening strategy yields covalent inhibitors that inactivate bifunctional DNA polymerase β by modifying lysine residues in different active site domains and prevent DNA binding.
ISSN:1439-4227
1439-7633
1439-7633
DOI:10.1002/cbic.202100247