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Patients with hepatocellular carcinoma (HCC) suffer from few treatment options and poor survival rates. Here we report that endonuclease VIII-like protein 3 (NEIL3) is overexpressed in HCC and correlates with poor survival. All six HCC cell lines investigated were dependent on NEIL3 catalytic activity for survival and prevention of senescence, while NEIL3 was dispensable for nontransformed cells. NEIL3-depleted HCC cell lines accumulated oxidative DNA lesions specifically at telomeres, resulting in telomere dysfunctional foci and 53BP1 foci formation. Following oxidative DNA damage during mitosis, NEIL3 relocated to telomeres and recruited apurinic endonuclease 1 (APE1), indicating activation of base excision repair. META-FISH revealed that NEIL3, but not NEIL1 or NEIL2, is required to initiate APE1 and polymerase beta (POLB)-dependent base excision repair at oxidized telomeres. Repeated exposure of NEIL3-depleted cells to oxidizing damage induced chromatin bridges and damaged telomeres. These results demonstrate a novel function for NEIL3 in repair of oxidative DNA damage at telomeres in mitosis, which is important to prevent senescence of HCC cells. Furthermore, these data suggest that NEIL3 could be a target for therapeutic intervention for HCC.Significance:This study describes compartmentalization of base excision repair during mitosis that is dependent on NEIL3, APE1, and POLB to repair oxidative damage accumulating at telomeres in hepatocellular carcinoma.

Supplementary Data from NEIL3 Prevents Senescence in Hepatocellular Carcinoma by Repairing Oxidative Lesions at Telomeres during Mitosis

While the repair of DNA double-strand breaks is known to be confined to different phases of the cell cycle and differentially activated at telomeres, less is known of compartmentalisation of base excision repair (BER). Here, we report that Endonuclease VIII like protein 3 (NEIL3) relocates to telomeres following oxidative DNA damage specifically during mitosis and recruits the APE1 to damaged telomeres. Using META-FISH, we demonstrate that NEIL3, but not NEIL1 or NEIL2, is required to initiate base excision repair at oxidised telomeres in mitotic cells, a process dependent on APE1 and Polβ. Repetitive exposure of oxidizing damage in NEIL3 depleted cells induced chromatin bridges and damaged telomeres. Interestingly, we identify that NEIL3 is elevated in Hepatocellular carcinoma (HCC), the most common type of a liver cancer, which correlates with poor survival. We demonstrate that HCC cell lines (6/6) depend on NEIL3 catalytic activity for survival and prevention of senescence, which is not the case for non-transformed cells where NEIL3 is dispensable. In conclusion, we demonstrate a novel function for NEIL3 in repair of oxidative DNA damage at telomeres in mitosis which is important to prevent senescence of HCC. Furthermore, these data suggest NEIL3 could be a target for therapeutic intervention of HCC.

Patients with hepatocellular carcinoma (HCC) suffer from few treatment options and poor survival rates. Here we report that endonuclease VIII-like protein 3 (NEIL3) is overexpressed in HCC and correlates with poor survival. All six HCC cell lines investigated were dependent on NEIL3 catalytic activity for survival and prevention of senescence, while NEIL3 was dispensable for nontransformed cells. NEIL3-depleted HCC cell lines accumulated oxidative DNA lesions specifically at telomeres, resulting in telomere dysfunctional foci and 53BP1 foci formation. Following oxidative DNA damage during mitosis, NEIL3 relocated to telomeres and recruited apurinic endonuclease 1 (APE1), indicating activation of base excision repair. META-FISH revealed that NEIL3, but not NEIL1 or NEIL2, is required to initiate APE1 and polymerase beta (POLB)-dependent base excision repair at oxidized telomeres. Repeated exposure of NEIL3-depleted cells to oxidizing damage induced chromatin bridges and damaged telomeres. These results demonstrate a novel function for NEIL3 in repair of oxidative DNA damage at telomeres in mitosis, which is important to prevent senescence of HCC cells. Furthermore, these data suggest that NEIL3 could be a target for therapeutic intervention for HCC. SIGNIFICANCE: This study describes compartmentalization of base excision repair during mitosis that is dependent on NEIL3, APE1, and POLB to repair oxidative damage accumulating at telomeres in hepatocellular carcinoma.

ObjectiveTo compared the prognosis between infants with biliary atresia (BA) who underwent living donor liver transplantation (LDLT) during 2006-2009 and 2010-2012 in the Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine and to evaluate the prognos is of LDLT performed during different periods. MethodsA retrospective analysis was performed on the clinical data of 101 infants with BA who underwent LDLT from October 2006 to December 2012. These patients were divided into 2006-2009 group and 2010-2012 group according to the year the procedure was performed. The two groups were compared in terms of preoperative general data, intraoperative status, and treatment outcome. The Kaplan-Meier method was used for survival analysis; measurement data were analyzed by t test, and enumeration data were analyzed by Fisher exact probability test and chi-square test. ResultsThe preoperative general data showed no significant difference between the two groups. Compared with the 2006-2009 group, the 2010-2012 group had significantly less intraoperative blood loss (t=2.05, P=0.04), a significantly shorter cold ischemia time of donor liver (t=3.25, P＜0.01), and significantly lower incidence of postoperative biliary complications (χ2=4.27, P=0.04), pulmonary infection (χ2=4.47, P=0.03), and acute rejection (P=0.03). The 2010-2012 group had significantly improved survival compared with the 2006-2009 group; the 1 and 2 year cumulative survival rates for the 2010-2012 group were 884% and 88.4%, respectively, versus 84.4% and 75% for the 2006-2009 group. ConclusionThe development of surgical techniques, improvement in perioperative management, and standardized follow-up can significantly increase the success rate of surgery and survival rate and reduce postoperative complications in BA patients.