Noncompetitive Inhibition of DNA Polymerase β by a Nonnative Nucleotide.

ABSTRACT: Base excision repair (BER) is a DNA repair pathway responsible for protecting the genome against modified nucleotides. DNA polymerase β (Pol β) participates in this process by removing the remnants of a damaged nucleotide and filling in the resulting gap. Pol β is overexpressed in some cancers and is synthetic lethal in cells deficient in BRCA1/2, providing additional impetus for identifying inhibitors of this enzyme. We report noncovalent Pol β inhibitors that are nonnative nucleotides. The inhibitors were identified via a combination of structural and biochemical analysis, as well as serendipity, from an initial library of covalent inhibitor candidates in which diversity was introduced sequentially at the C3'- and C5-positions of pyrimidine nucleotides. The molecules are among the most p

SUBMITTER: Howlader AH 

PROVIDER: S-EPMC12431629 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature