CHD1L Regulates Cell Survival in Breast Cancer and Its Inhibition by OTI-611 Impedes the DNA Damage Response and Induces PARthanatos.

ABSTRACT: The Chromodomain helicase DNA-binding protein 1-like (CHD1L) is a nucleosome remodeling enzyme, which plays a key role in chromatin relaxation during the DNA damage response. Genome editing has shown that deletion of CHD1L sensitizes cells to PARPi, but the effect of its pharmacological inhibition has not been defined. Triple-negative breast cancer SUM149PT, HCC1937, and MDA-MB-231 cells were used to assess the mechanism of action of the CHD1Li OTI-611. Cytotoxicity as a single agent or in combination with standard-of-care treatments was assessed in tumor organoids. Immunofluorescence was used to assess the translocation of PAR and AIF to the cytoplasm or the nucleus and to study markers of DNA damage or apoptosis. Trapping of PARP1/2 or CHD1L onto chromatin was also assessed by in situ su

SUBMITTER: Sala R 

PROVIDER: S-EPMC11354643 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature