Defective DNA damage response and repair in liver cells expressing hepatitis B virus surface antigen

Abstract

Hepatitis B virus (HBV) is implicated in liver cancer. The aim of this study was to find out whether HBV or its components [HBV surface antigen (HBsAg), HBV core protein (HBc), and HBV X protein (HBx)] could interfere with the host DNA damage response and repair pathway. The full HBV genome or individual HBV open-reading frame (ORF) was introduced into HepG2 cells to examine the effect on host genomic stability, DNA repair efficacy in response to double-strand DNA damage, and DNA damage-induced cell death. Responses to apoptosis induction in the HBV ORF-transfected HepG2 cells were also compared with those in HBV-positive and HBV-negative human hepatocellular carcinoma (HCC) cells. In the absence of HBV replication, accumulation of HBsAg in liver cells without other HBV proteins enhanced DNA repair protein and tumor suppressor promyelocytic leukemia (PML) degradation, which resulted in resistance to apoptosis induction and deficient double-strand DNA repair. However, HBsAg-positive cells exhibited increased cell death with exposure to the poly(ADP-ribose) polymerase inhibitor that blocks single-strand DNA repair. These results indicate that suppression of PML by HBsAg disrupts cellular mechanisms that respond to double-strand DNA damage for DNA repair or apoptosis induction, which may facilitate hepatocarcinogenesis and open up a synthetic lethality strategy for HBsAg-positive HCC treatment.

Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

“…2b, c). Thus, we interpreted that c-H2AX-positive cells in pHBV-X 2 cells may come from HBV surface antigen (HBs) expression because it was recently reported that HBs could also induce DNA damage (Chung, 2013). Together, our data demonstrate that HBx is one of the major factors causing DSBs in HBV-related liver cells.…”

Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

“…Genomic instability including telomere erosion [12–14], chromosome segregation defects [15, 16], and alterations in the DDR pathways [17, 18] has been regarded as a common feature of human HCC. Various genetic alterations accumulate during hepatocarcinogenesis that change the signal transduction network [19].…”

“…Studies of the metabolism of AFB1 revealed that the compound is activated to its electrophilic DNA-binding form through an epoxidation pathway. Furthermore, activation and DNA binding produces identical DNA adduct profiles, with the N7 position of guanine representing the only site of adduct formation [18]. In regions where exposure to AFB1 and chronic exposure to HBV are frequently concomitant, there is a high incidence of HCC that often harbors TP53 mutations [54].…”

“…Binding of HBx on TP53 leads to inhibition of TP53-dependent DNA repair, thereby DNA damage accumulation in HBV-infected cells, and subsequently depressed TP53-dependent apoptosis [183, 185, 186]. Furthermore, recent study has also indicated that HBsAg disrupts promyelocytic leukemia- (PML-) mediated DSB HR repair or apoptosis, which may facilitate hepatocarcinogenesis [18]. Based on these data, it has been suggested that HBV may affect a wide range of TP53 functions [183].…”

Hepatitis B virus induces RNR-R2 expression via DNA damage response activation

“…HBV was reported to attenuate DNA damage repair [32][33][34]. We asked whether HBV affects repair in our system of quiescent cells.…”