Publication Date
6-1-2021
Journal
Science Advances
DOI
10.1126/sciadv.abe2846
PMID
34144978
PMCID
PMC8213236
PubMedCentral® Posted Date
6-18-2021
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Chromosome Fragility, DNA, DNA Replication, DNA, Cruciform, Escherichia coli, Genomic Instability, Humans, Neoplasms
Abstract
Chromosomal fragile sites are implicated in promoting genome instability, which drives cancers and neurological diseases. Yet, the causes and mechanisms of chromosome fragility remain speculative. Here, we identify three spontaneous fragile sites in the Escherichia coli genome and define their DNA damage and repair intermediates at high resolution. We find that all three sites, all in the region of replication termination, display recurrent four-way DNA or Holliday junctions (HJs) and recurrent DNA breaks. Homology-directed double-strand break repair generates the recurrent HJs at all of these sites; however, distinct mechanisms of DNA breakage are implicated: replication fork collapse at natural replication barriers and, unexpectedly, frequent shearing of unsegregated sister chromosomes at cell division. We propose that mechanisms such as both of these may occur ubiquitously, including in humans, and may constitute some of the earliest events that underlie somatic cell mosaicism, cancers, and other diseases of genome instability.
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