2. Academic Validation
  3. NEIL3 Prevents Senescence in Hepatocellular Carcinoma by Repairing Oxidative Lesions at Telomeres during Mitosis

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

  • Cancer Res. 2021 Aug 1;81(15):4079-4093. doi: 10.1158/0008-5472.CAN-20-1028.
Zhenjun Zhao 1 2,  Helge Gad  # 1 3,  Carlos Benitez-Buelga 1,  Kumar Sanjiv 1,  Hua Xiangwei 4,  He Kang 2,  Mingxuan Feng 2,  Zhicong Zhao  # 2,  Ulrika Warpman Berglund 1,  Qiang Xia 5,  Thomas Helleday 6 3
Affiliations

Affiliations

  • 1 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
  • 2 Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
  • 4 Organ Transplantation Center, the Affiliated Hospital of Qingdao University, Qingdao, China.
  • 5 Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. thomas.helleday@scilifelab.se xiaqiang@shsmu.edu.cn.
  • 6 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. thomas.helleday@scilifelab.se xiaqiang@shsmu.edu.cn.
  • # Contributed equally.
PMID: 34045188 DOI: 10.1158/0008-5472.CAN-20-1028
Abstract

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.

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