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

Mohebi, Saed, Mizuno, Ken'Ichi, Watson, Adam, Carr, Antony M and Murray, Johanne M (2015) Checkpoints are blind to replication restart and recombination intermediates that result in gross chromosomal rearrangements. Nature Communications, 6. p. 6357. ISSN 2041-1723

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: Helen Webb - Library
Date Deposited: 03 Jun 2015 07:30
Last Modified: 06 Mar 2017 23:16
URI: http://sro.sussex.ac.uk/id/eprint/54256

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Project NameSussex Project NumberFunderFunder Ref
UnsetUnsetAICR10-0273
UnsetUnsetCANCER RESEARCH UKC9601/A9484
Replication fork stability and fork restartG0745MRC-MEDICAL RESEARCH COUNCILG1100074-E01/1
Single Molecule Imaging of the DNA Damage Response in Live CellsG0250EUROPEAN UNION268788