NEIL3-mediated mitotic base excision repair of oxidative lesions at telomeres prevents senescence in hepatocellular carcinoma

Abstract

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.