Acute methylmercury exposure induces inactivation of ATR pathway and enhancement of DNA replication stress through degradation of Rad17

Abstract

Methylmercury (MeHg) is a neurotoxic chemical of significant public health concern. Acute exposure to MeHg causes inhibition of cellular proliferation and DNA replication in cellular and animal models, and impedes S-phase entry and progression in several types of primary and cultured cells. However, the effect of MeHg on the DNA damage response remains unknown. The ATM and ATR pathways are two major components of the DNA damage response that regulate cell cycle progression. Here we report that acute MeHg exposure enhanced DNA replication stress in S phase. MeHg also inhibited the kinase activity of ATR, suggesting that replication forks collapsed in S phase. Moreover, MeHg promoted the degradation of Rad17 as a possible mechanism underlying the inactivation of ATR. These results suggest a novel connection between acute MeHg exposure and the ATR pathway, providing insight into a yet unidentified mechanism of the inactivation of Rad17 and the ATR pathway.