Profiling DNA damage response following mitotic perturbations

TY - JOUR

T1 - Profiling DNA damage response following mitotic perturbations

AU - Pedersen, Ronni Sølvhøi

AU - Karemore, Gopal

AU - Gudjonsson, Thorkell

AU - Rask, Maj-Britt

AU - Neumann, Beate

AU - Hériché, Jean-Karim

AU - Pepperkok, Rainer

AU - Ellenberg, Jan

AU - Gerlich, Daniel W

AU - Lukas, Jiri

AU - Lukas, Claudia

PY - 2016/12/15

Y1 - 2016/12/15

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms13887

DO - 10.1038/ncomms13887

M3 - Journal article

C2 - 27976684

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 13887

ER -