Abstract

Cancer is a life-threatening disease that affects one in three people. Although most cases are sporadic, cancer risk can be increased by genetic factors. It remains unknown why certain genes predispose for specific forms of cancer only, such as checkpoint protein 2 (CHK2), in which gene mutations convey up to twofold higher risk for breast cancer but do not increase lung cancer risk. We have investigated the role of CHK2 and the related kinase checkpoint protein 1 (CHK1) in cell cycle regulation in primary breast and lung primary epithelial cells. At the molecular level, CHK1 activity was higher in lung cells, whereas CHK2 was more active in breast cells. Inhibition of CHK1 profoundly disrupted the cell cycle profile in both lung and breast cells, whereas breast cells were more sensitive toward inhibition of CHK2. Finally, we provide evidence that breast cells require CHK2 to induce a G2–M cell cycle arrest in response of DNA damage, whereas lung cells can partially compensate for the loss of CHK2. Our results provide an explanation as to why CHK2 germline mutations predispose for breast cancer but not for lung cancer.

Details

Title
Cell-type-specific role of CHK2 in mediating DNA damage-induced G2 cell cycle arrest
Author
van Jaarsveld Marijn T M 1 ; Deng Difan 1 ; Ordoñez-Rueda, Diana 2 ; Paulsen Malte 2 ; Wiemer, Erik A, C 3   VIAFID ORCID Logo  ; Zi Zhike 4   VIAFID ORCID Logo 

 Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany 
 European Molecular Biology Laboratory, Flow Cytometry Core Facility, Heidelberg, Germany (GRID:grid.4709.a) (ISNI:0000 0004 0495 846X) 
 Erasmus University Medical Center, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
 Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Berlin, Germany (GRID:grid.5645.2); German Federal Institute for Risk Assessment, Department of Experimental Toxicology and ZEBET, Berlin, Germany (GRID:grid.417830.9) (ISNI:0000 0000 8852 3623) 
Publication year
2020
Publication date
Mar 2020
Publisher
Nature Publishing Group
e-ISSN
21579024
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2376946199
Copyright
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.