ID3 deficiency alters chromatin accessibility at DSB sites and enhances vulnerability to HDAC inhibition
Menée à l'aide d'une lignée cellulaire d'ostéosarcome intégrant un système d'induction de cassures double-brin de l'ADN, cette étude met en évidence un mécanisme par lequel la défaillance de l'inhibiteur ID3 altère l'accessibilité aux sites des cassures double brin et sensibilise les cellules cancéreuses à l'inhibition de l'histone désacétylase
The inhibitor of DNA-binding 3 (ID3) plays a crucial role in DNA double-strand break (DSB) repair. We previously reported that ID3 loss reduced chromatin accessibility at DNA repair gene promoters, yet its exact role in DNA repair via chromatin regulation remains elusive. Using the AID-DIvA cell system with inducible DSBs, we show that ID3 directly regulates chromatin accessibility at DSB sites, as demonstrated by reduced chromatin accessibility and lower H3K27ac levels in ID3-knockout (KO) cells. Loss of ID3 renders cells susceptible to histone deacetylase (HDAC) inhibition, particularly to the Class I HDAC inhibitor, leading to the accumulation of unrepaired DSBs and delayed cell cycle progression. Transcriptome and proteome analyses revealed that HDAC inhibition in ID3-KO cells results in the downregulation of gene sets involved in the regulation of cell cycle and cell division. The synthetic lethality observed between ID3 loss and Class I HDAC inhibition underscores a novel therapeutic vulnerability in ID3-deficient cancers, driven by compounded defects in chromatin remodeling, cell cycle, and DNA repair. Our study provides new insights into the relationship between chromatin regulation and genome stability, with implications for targeted cancer therapies.
International Journal of Cancer , article en libre accès, 2026