A limited number of double-strand DNA breaks is sufficient to delay cell cycle progression

Abstract DNA damaging agents cause a variety of lesions, of which DNA double-strand breaks (DSBs) are the most genotoxic. Unbiased approaches aimed at investigating the relationship between the number of DSBs and outcome of the DNA damage response have been challenging due to the random nature in wh...

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Bibliographic Details
Published in:Nucleic acids research 2018-11, Vol.46 (19), p.10132-10144
Main Authors: van den Berg, Jeroen, G. Manjón, Anna, Kielbassa, Karoline, Feringa, Femke M, Freire, Raimundo, Medema, René H
Format: Article
Language:English
Subjects:
Aneuploidy
Cell Cycle - genetics
Cell Cycle Checkpoints - genetics
Cell Line
CRISPR-Cas Systems
DNA Breaks, Double-Stranded
DNA Damage
DNA Repair
Genome Integrity, Repair and
Genome, Human - genetics
Humans
Mitosis - genetics
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Summary:Abstract DNA damaging agents cause a variety of lesions, of which DNA double-strand breaks (DSBs) are the most genotoxic. Unbiased approaches aimed at investigating the relationship between the number of DSBs and outcome of the DNA damage response have been challenging due to the random nature in which damage is induced by classical DNA damaging agents. Here, we describe a CRISPR/Cas9-based system that permits us to efficiently introduce DSBs at defined sites in the genome. Using this system, we show that a guide RNA targeting only a single site in the human genome can trigger a checkpoint response that is potent enough to delay cell cycle progression. Abrogation of this checkpoint leads to DNA breaks in mitosis which gives rise to aneuploid progeny.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gky786