hDNA2 nuclease/helicase promotes centromeric DNA replication and genome stability

• Zhengke Li ^[3] ; Bochao Liu ^[4] ; Weiwei Jin ^[5] ; Xiwei Wu ^[6] ; Mian Zhou ^[3] ; Vincent Zewen Liu ^[1] ; Ajay Goel ^[2] ; Zhiyuan Shen ^[4] ; Li Zheng ^[3] ; Binghui Shen ^[3]
  1. [1] Columbia University

     Columbia University

     Estados Unidos

     
  2. [2] Baylor University Medical Center

     Baylor University Medical Center

     Estados Unidos

     
  3. [3] 1 Department of Cancer Genetics and Epigenetics Beckman Research Institute City of Hope Duarte CA USA
  4. [4] 2 Department of Radiation Oncology Rutgers Cancer Institute of New Jersey Rutgers Robert Wood Johnson Medical School Rutgers, the State University of New Jersey New Brunswick NJ USA
  5. [5] 1 Department of Cancer Genetics and Epigenetics Beckman Research Institute City of Hope Duarte CA USA; 3 Department of Gastroenterology & Pancreatic Surgery Zhejiang Provincial People's Hospital Hangzhou Zhejiang China
  6. [6] 4 Department of Molecular and Cellular Biology Beckman Research Institute City of Hope Duarte CA USA

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 14, 2018, págs. 6-6
• Idioma: inglés
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• Resumen

  • DNA2 is a nuclease/helicase that is involved in Okazaki fragment maturation, replication fork processing, and end resection of DNA double‐strand breaks. Similar such helicase activity for resolving secondary structures and structure‐specific nuclease activity are needed during DNA replication to process the chromosome‐specific higher order repeat units present in the centromeres of human chromosomes. Here, we show that DNA2 binds preferentially to centromeric DNA. The nuclease and helicase activities of DNA2 are both essential for resolution of DNA structural obstacles to facilitate DNA replication fork movement. Loss of DNA2‐mediated clean‐up mechanisms impairs centromeric DNA replication and CENP‐A deposition, leading to activation of the ATR DNA damage checkpoints at centromeric DNA regions and late‐S/G2 cell cycle arrest. Cells that escape arrest show impaired metaphase plate formation and abnormal chromosomal segregation. Furthermore, the DNA2 inhibitor C5 mimics DNA2 knockout and synergistically kills cancer cells when combined with an ATR inhibitor. These findings provide mechanistic insights into how DNA2 supports replication of centromeric DNA and give further insights into new therapeutic strategies.