Chromatin-Associated SIN3B Protects Cancer Cells from Genotoxic Stress-Induced Apoptosis and Dictates DNA Damage Repair Pathway Choice

Abstract

Abstract Transcription and DNA damage repair act in a coordinated manner. The scaffolding protein SIN3B serves as a transcriptional co-repressor of hundreds of cell cycle–related genes. However, the contribution of SIN3B during the DNA damage response remains unknown. Here, we show that SIN3B inactivation delays the resolution of DNA double-strand breaks and sensitizes cancer cells to DNA-damaging agents, including the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, SIN3B is rapidly recruited to DNA damage sites where it directs the accumulation of Mediator of DNA Damage Checkpoint 1 (MDC1). In addition, we show that SIN3B inactivation favors the engagement of the alternative nonhomologous end joining (NHEJ) repair pathway over the canonical NHEJ. Altogether, our findings impute an unexpected function for the transcriptional co-repressor SIN3B as a gatekeeper of genomic integrity and a determining factor in the DNA repair choice pathway, and point to the inhibition of the SIN3B chromatin-modifying complex as a novel therapeutic vulnerability in cancer cells. Implications: Identifying SIN3B as a modulator of DNA damage repair choice provides novel potential therapeutic avenues to sensitize cancer cells to cytotoxic therapies.