Checkpoints are blind to replication restart and recombination intermediates that result in gross chromosomal rearrangements

Saed Mohebi, Ken’Ichi Mizuno, Adam Watson, Antony M. Carr () and Johanne M. Murray ()
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Saed Mohebi: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer
Ken’Ichi Mizuno: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer
Adam Watson: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer
Antony M. Carr: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer
Johanne M. Murray: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: Abstract Replication fork inactivation can be overcome by homologous recombination, but this can cause gross chromosomal rearrangements that subsequently missegregate at mitosis, driving further chromosome instability. It is unclear when the chromosome rearrangements are generated and whether individual replication problems or the resulting recombination intermediates delay the cell cycle. Here we have investigated checkpoint activation during HR-dependent replication restart using a site-specific replication fork-arrest system. Analysis during a single cell cycle shows that HR-dependent replication intermediates arise in S phase, shortly after replication arrest, and are resolved into acentric and dicentric chromosomes in G2. Despite this, cells progress into mitosis without delay. Neither the DNA damage nor the intra-S phase checkpoints are activated in the first cell cycle, demonstrating that these checkpoints are blind to replication and recombination intermediates as well as to rearranged chromosomes. The dicentrics form anaphase bridges that subsequently break, inducing checkpoint activation in the second cell cycle.

Date: 2015
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DOI: 10.1038/ncomms7357

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