ncomms7357.pdf (4.14 MB)
Checkpoints are blind to replication restart and recombination intermediates that result in gross chromosomal rearrangements
journal contribution
posted on 2023-06-08, 20:59 authored by Saed Mohebi, Ken'Ichi Mizuno, Adam WatsonAdam Watson, Antony CarrAntony Carr, Jo MurrayReplication 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.
Funding
AICR; 10-0273
Single Molecule Imaging of the DNA Damage Response in Live Cells; G0250; EUROPEAN UNION; 268788
CANCER RESEARCH UK; C9601/A9484
Replication fork stability and fork restart; G0745; MRC-MEDICAL RESEARCH COUNCIL; G1100074-E01/1
History
Publication status
- Published
File Version
- Published version
Journal
Nature CommunicationsISSN
2041-1723Publisher
Nature Publishing GroupExternal DOI
Issue
1Volume
6Article number
a6357Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2015-06-03First Open Access (FOA) Date
2015-06-03First Compliant Deposit (FCD) Date
2015-06-02Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC