The faithful transmission of genetic information is crucial for life. It relies on the precise process of DNA replication and on a robust DNA damage response to counteract potential endogenous and exogenous threats. Perturbing this system uncovers critical functions of factors involved in maintaining genome stability. This study explores the consequences of PARG inhibition on cell cycle progression, replication dynamics, DNA damage accumulation, and cell viability, specifically in the context of cancer cell lines.

We investigate the mechanisms triggered by PARG inhibition, which is particularly detrimental for cells exhibiting oncogene-induced replication stress. In fact, inhibiting PARG in cells overexpressing Cyclin E leads to cell cycle defects and DNA damage accumulation. Furthermore, our research shows a critical synergy between PARG and ATR inhibition, uncovering a crucial role for the ATR-dependent pathway to respond to the absence of PARG. Additionally, the chromatin remodeler SMARCAD1 seems to be important for mitigating the damage accumulated in PARG-inhibited cells.

The results of this work provide insights into the mechanisms governing the cellular response to PARG inhibition-induced replication stress, highlighting its context-dependent consequences.