Abstract

Cdc7-Dbf4 kinase plays a key role in the initiation of DNA replication and contributes to the replication stress in cancer. The activity of human Cdc7-Dbf4 kinase remains active and acts as an effector of checkpoint under replication stress. However, the downstream targets of Cdc7-Dbf4 contributed to checkpoint regulation and replication stress-support function in cancer are not fully identified. In this work, we showed that aberrant Cdc7-Dbf4 induces DNA lesions that activate ATM/ATR-mediated checkpoint and homologous recombination (HR) DNA repair. Using a phosphoproteome approach, we identified HSP90-S164 as a target of Cdc7-Dbf4 in vitro and in vivo. The phosphorylation of HSP90-S164 by Cdc7-Dbf4 is required for the stability of HSP90-HCLK2-MRN complex and the function of ATM/ATR signaling cascade and HR DNA repair. In clinically, the phosphorylation of HSP90-S164 indeed is increased in oral cancer patients. Our results indicate that aberrant Cdc7-Dbf4 enhances replication stress tolerance by rewiring ATR/ATM mediated HR repair through HSP90-S164 phosphorylation and by promoting recovery from replication stress. We provide a new solution to a subtyping of cancer patients with dominant ATR/HSP90 expression by combining inhibitors of ATR-Chk1, HSP90, or Cdc7 in cancer combination therapy.

Details

Title
Cdc7-Dbf4-mediated phosphorylation of HSP90-S164 stabilizes HSP90-HCLK2-MRN complex to enhance ATR/ATM signaling that overcomes replication stress in cancer
Author
An Ning Cheng 1 ; Chi-Chen, Fan 2 ; Yu-Kang, Lo 3 ; Cheng-Liang, Kuo 3 ; Hui-Chun, Wang 4 ; I-Hsin, Lien 3 ; Shu-Yu, Lin 5 ; Chung-Hsing, Chen 3 ; Shih Sheng Jiang 3 ; I-Shou, Chang 3 ; Hsueh-Fen Juan 6   VIAFID ORCID Logo  ; Ping-Chiang Lyu 7 ; Lee, Alan Yueh-Luen 8   VIAFID ORCID Logo 

1  National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan; Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan 
2  Superintendent Office, Mackay Memorial Hospital, Taipei, Taiwan; Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu, Taiwan 
3  National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan 
4  Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan 
5  Common Mass Spectrometry Facilities, Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan 
6  Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan; Department of Life Science, National Taiwan University, Taipei, Taiwan 
7  Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan 
8  National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan 
Pages
1-15
Publication year
2017
Publication date
Dec 2017
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-017-17126-2
ProQuest document ID
1983425741
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.