The chromatin associated Sin3B is a critical regulator of DNA damage repair through the engagement of the Non-Homologous End Joining

Transcription and DNA damage repair act in a coordinated manner. The scaffolding protein Sin3B serves as a transcriptional corepressor of hundreds of cell-cycle-related genes. However, the role of Sin3B during the DNA damage response still remains unknown. Here, we show that Sin3B depletion delays the resolution of DNA double-strand breaks (DSBs) and sensitizes cells to diverse DNA-damaging agents, including cisplatin and doxorubicin. Furthermore, Sin3B is rapidly recruited to DNA damage sites and interacts with other DDR proteins. Mechanistically, Sin3B promotes non-homologous end joining DNA repair by directing the accumulation of MDC1 at DBSs. Altogether, our findings impute an unexpected function for the transcriptional co-repressor Sin3B as a gatekeeper of genomic integrity, and point to the inhibition of the Sin3B chromatin modifying complex as a novel therapeutic vulnerability in cancer cells. ### Competing Interest Statement The authors have declared no competing interest.