The BRUCE‐ATR signaling axis is required for accurate DNA replication and suppression of liver cancer development

Abstract

Replication fork stability during DNA replication is vital for maintenance of genomic stability and suppression of cancer development in mammals. ATR is a master regulatory kinase that activates the replication stress response to overcome replication barriers. While many downstream effectors of ATR have been established, the upstream regulators of ATR and the impact of such regulation on liver cancer remain unclear. The ubiquitin conjugase BRUCE is a guardian of chromosome integrity and activator of ATM signaling which promotes DNA double‐strand break repair via homologous recombination. Here we demonstrate new functions for BRUCE in ATR activation in vitro and liver tumor suppression in vivo. BRUCE is recruited to induced DNA damage sites. Depletion of BRUCE inhibited multiple ATR‐dependent signaling events during replication stress, including activation of ATR itself, phosphorylation of its downstream targets CHK1 and RPA, and the mono‐ubiquitination of FANCD2. Consequently, BRUCE deficiency resulted in stalled DNA replication forks and increased firing of new replication origins. The in vivo impact of BRUCE loss on liver tumorigenesis was determined using the hepatocellular carcinoma model induced by genotoxin Diethylnitrosamine. Liver‐specific knockout of murine Bruce impaired ATR activation and exacerbated inflammation, fibrosis and hepatocellular carcinoma, which exhibited a trabecular architecture, closely resembling human HCC. In humans, the clinical relevance of BRUCE downregulation in liver disease was found in hepatitis, cirrhosis and hepatocellular carcinoma specimens and deleterious somatic mutations of the Bruce gene was found in human hepatocellular carcinoma in TCGA database. Conclusion: These findings establish a new BRUCE‐ATR signaling axis in accurate DNA replication and suppression of liver cancer in mice and humans and provides a clinically relevant HCC mouse model.

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