Profiling DNA damage response following mitotic perturbations

Ronni S. Pedersen, Gopal Karemore, Thorkell Gudjonsson, Maj-Britt Rask, Beate Neumann, Jean-Karim Hériché, Rainer Pepperkok, Jan Ellenberg, Daniel W. Gerlich, Jiri Lukas () and Claudia Lukas ()
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Ronni S. Pedersen: Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Gopal Karemore: Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Thorkell Gudjonsson: Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Maj-Britt Rask: Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Beate Neumann: Advanced Light Microscopy Facility, European Molecular Biology Laboratory
Jean-Karim Hériché: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory
Rainer Pepperkok: Advanced Light Microscopy Facility, European Molecular Biology Laboratory
Jan Ellenberg: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory
Daniel W. Gerlich: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC)
Jiri Lukas: Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Claudia Lukas: Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Genome integrity relies on precise coordination between DNA replication and chromosome segregation. Whereas replication stress attracted much attention, the consequences of mitotic perturbations for genome integrity are less understood. Here, we knockdown 47 validated mitotic regulators to show that a broad spectrum of mitotic errors correlates with increased DNA breakage in daughter cells. Unexpectedly, we find that only a subset of these correlations are functionally linked. We identify the genuine mitosis-born DNA damage events and sub-classify them according to penetrance of the observed phenotypes. To demonstrate the potential of this resource, we show that DNA breakage after cytokinesis failure is preceded by replication stress, which mounts during consecutive cell cycles and coincides with decreased proliferation. Together, our results provide a resource to gauge the magnitude and dynamics of DNA breakage associated with mitotic aberrations and suggest that replication stress might limit propagation of cells with abnormal karyotypes.

Date: 2016
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DOI: 10.1038/ncomms13887

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