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Profiling DNA damage response following mitotic perturbations

Profiling DNA damage response following mitotic perturbations

Title: Profiling DNA damage response following mitotic perturbations
Author: Pedersen, Ronni S.
Karemore, Gopal
Guðjónsson, Þorkell
Rask, Maj-Britt
Neumann, Beate
Hériché, Jean-Karim
Pepperkok, Rainer
Ellenberg, Jan
Gerlich, Daniel W.
Lukas, Jiri
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Date: 2016-12-15
Language: English
Scope: 13887
University/Institute: Háskóli Íslands
University of Iceland
School: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Department: Læknadeild (HÍ)
Faculty of Medicine (UI)
Series: Nature Communications;7
ISSN: 2041-1723
DOI: 10.1038/ncomms13887
Subject: DNA replication; Double-strand DNA breaks; Mitosis; DNA rannsóknir
URI: https://hdl.handle.net/20.500.11815/380

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S. Pedersen, R., Karemore, G., Gudjonsson, T., Rask, M.-B., Neumann, B., Hériché, J.-K., . . . Lukas, C. (2016). Profiling DNA damage response following mitotic perturbations. 7, 13887. doi:10.1038/ncomms13887


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.


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