A Selective Small Molecule DNA2 Inhibitor for Sensitization of Human Cancer Cells to Chemotherapy

Wenpeng Liu, Mian Zhou, Zhengke Li, Hongzhi Li, Piotr Polaczek, Huifang Dai, Qiong Wu, Changwei Liu, Kenneth K. Karanja, Vencat Popuri, Shu Ou Shan, Katharina Schlacher, Li Zheng, Judith L. Campbell, Binghui Shen

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Cancer cells frequently up-regulate DNA replication and repair proteins such as the multifunctional DNA2 nuclease/helicase, counteracting DNA damage due to replication stress and promoting survival. Therefore, we hypothesized that blocking both DNA replication and repair by inhibiting the bifunctional DNA2 could be a potent strategy to sensitize cancer cells to stresses from radiation or chemotherapeutic agents. We show that homozygous deletion of DNA2 sensitizes cells to ionizing radiation and camptothecin (CPT). Using a virtual high throughput screen, we identify 4-hydroxy-8-nitroquinoline-3-carboxylic acid (C5) as an effective and selective inhibitor of DNA2. Mutagenesis and biochemical analysis define the C5 binding pocket at a DNA-binding motif that is shared by the nuclease and helicase activities, consistent with structural studies that suggest that DNA binding to the helicase domain is necessary for nuclease activity. C5 targets the known functions of DNA2 in vivo: C5 inhibits resection at stalled forks as well as reducing recombination. C5 is an even more potent inhibitor of restart of stalled DNA replication forks and over-resection of nascent DNA in cells defective in replication fork protection, including BRCA2 and BOD1L. C5 sensitizes cells to CPT and synergizes with PARP inhibitors.

Original languageEnglish (US)
Pages (from-to)73-86
Number of pages14
JournalEBioMedicine
Volume6
DOIs
StatePublished - Apr 1 2016

Bibliographical note

Publisher Copyright:
© 2016 The Authors.

Keywords

  • Camptothecin
  • Cancer
  • Chemotherapy
  • DNA binding
  • DNA end resection
  • DNA replicatoin fork protection
  • DNA2 inhibitor
  • Helicase
  • Nuclease
  • PARP inhibitor
  • Sensitizer

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