Cadmium disrupts the DNA damage response by destabilizing RNF168.

Cadmium (Cd) is a dispensable element for the human body and is usually considered a carcinogen. Occupational and environmental Cd exposure leads to sustained cellular proliferation in some tissues and tumorigenesis via an unclear mechanism. Here, we evaluated the role of Cd in the DNA damage response (DDR). We found that Cd exposure causes extensive DNA double-strand breaks (DSBs) and prevents accumulation of ubiquitination signals at these sites of DNA damage. Cd treatment compromises 53BP1 and BRCA1 recruitment to DSBs induced by itself or DNA damaging agents and partially inactivates the G2/M checkpoint. Mechanistically, Cd directly binds to the E3 ubiquitin ligase RNF168, induces the ubiquitin-proteasome pathway that mediates RNF168 degradation and suppresses RNF168 ubiquitin-ligase activity in vitro. Our study raises the possibility that Cd may target RNF168 to disrupt proper DSB signaling in cultured cells. This pathway may represent a novel mechanism for carcinogenesis induced by Cd.