DNA polymerase beta connects tumorigenicity with the circadian clock in liver cancer through the epigenetic demethylation of Per1

Abstract

Abstract The circadian-controlled DNA repair exhibits a strong diurnal rhythm. Disruption in circadian clock and DNA repair is closely linked with hepatocellular carcinoma (HCC) progression, but the mechanism remains unknown. Here, we show that polymerase beta (Polb), a critical enzyme in the DNA base excision repair pathway, is rhythmically expressed at the translational level in mouse livers. Hepatic Polb dysfunction dampens clock homeostasis, whereas retards HCC progression, through methylation of the 4th CpG island on the 5'UTR of clock gene Per1. Clinically, POLB is overexpressed in human PolbHCC samples and positively associated with poor prognosis. Furthermore, the hepatic rhythmicity of Polb protein expression is orchestrated by Calreticulin (Calr). Our findings provide important insights into the molecular mechanism underlying the synergy between clock and food signals on the Polb-driven BER system and reveal new clock-dependent carcinogenetic effects of Polb. Therefore, chronobiological modulation of Polb may help to promote precise interventions for HCC.