Small-Molecule Inhibition of CBX4/7 Hypersensitises Homologous Recombination-Impaired Cancer to Radiation by Compromising CtIP-Mediated DNA End Resection.

ABSTRACT: The therapeutic targeting of DNA repair pathways is an emerging concept in cancer treatment. Compounds that target specific DNA repair processes, such as those mending DNA double-strand breaks (DSBs), are therefore of therapeutic interest. UNC3866 is a small molecule that targets CBX4, a chromobox protein, and a SUMO E3 ligase. As a key modulator of DNA end resection-a prerequisite for DSB repair by homologous recombination (HR)-CBX4 promotes the functions of the DNA resection factor CtIP. Here, we show that treatment with UNC3866 markedly sensitises HR-deficient, NHEJ-hyperactive cancer cells to ionising radiation (IR), while it is non-toxic in selected HR-proficient cells. Consistent with UNC3866 targeting CtIP functions, it inhibits end-resection-dependent DNA repair including HR, alter

SUBMITTER: Osborne HC 

PROVIDER: S-EPMC11172190 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature