HP1 enhances radio- and chemotherapy resistance in osteosarcoma via PARP1-dependent transcriptional repression and HR repair.

Osteosarcoma is a primary malignant bone tumour with an unsatisfactory prognosis, and individualised and comprehensive treatment is needed. HP1 (α/β/γ) is an important heterochromatin protein involved in transcriptional regulation and is also involved in the DNA damage response (DDR). However, little is known about the participation of HP1 in DNA damage-induced transcriptional repression. In this study, HP1 proteins were shown to be involved in DNA damage-mediated transcriptional repression at the very onset of DNA damage. Mechanistically, HP1 proteins were recruited to DNA damage sites by interacting with and being covalently PARylated by PARP1. This process increased H2AK119Ub, which ultimately led to the inactivation of RNA Pol II to achieve transcriptional suppression. Silencing HP1 led to a weakening of PARP1 recruitment and homologous recombination (HR) repair. Concurrently, HP1γ (CBX3) knockdown resulted in an increased the sensitivity of osteosarcoma cells to radiotherapy, chemotherapy and PARP1 inhibitors. The results of the study demonstrated the involvement of HP1 in the DDR via covalent PARylation by PARP1, resulting in the suppression of transcription and the promotion of HR repair. Overall, these results identify a new molecular mechanism of DNA damage-induced transcriptional repression and provide a theoretical basis for the potential application of DNA damage-induced transcriptional repression in the treatment of osteosarcoma.