title: Avoiding chromosome pathology when replication forks collide.
abstract: Chromosome duplication normally initiates through the assembly of replication fork complexes at defined origins. DNA synthesis by any one fork is thought to cease when it meets another travelling in the opposite direction, at which stage the replication machinery may simply dissociate before the nascent strands are finally ligated. But what actually happens is not clear. Here we present evidence consistent with the idea that every fork collision has the potential to threaten genomic integrity. In Escherichia coli this threat is kept at bay by RecG DNA translocase and by single-strand DNA exonucleases. Without RecG, replication initiates where forks meet through a replisome assembly mechanism normally associated with fork repair, replication restart and recombination, establishing new forks with the potential to sustain cell growth and division without an active origin. This potential is realized when roadblocks to fork progression are reduced or eliminated. It relies on the chromosome being circular, reinforcing the idea that replication initiation is triggered repeatedly by fork collision. The results reported raise the question of whether replication fork collisions have pathogenic potential for organisms that exploit several origins to replicate each chromosome.
authors.affiliation: Centre for Genetics and Genomics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK. christian.rudolph@brunel.ac.uk
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Rudolph
authors.forename: Amy L
authors.initials: AL
authors.lastname: Upton
authors.forename: Anna
authors.initials: A
authors.lastname: Stockum
authors.forename: Conrad A
authors.initials: CA
authors.lastname: Nieduszynski
authors.forename: Robert G
authors.initials: RG
authors.lastname: Lloyd
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism; D001435:Bacteriophages / Q000235:genetics / Q000502:physiology; D002876:Chromosomes, Bacterial / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism; D004261:DNA Replication; D004269:DNA, Bacterial; D004270:DNA, Circular; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics* / Q000254:growth & development / Q000821:virology; D029968:Escherichia coli Proteins / Q000378:metabolism; D043211:Exodeoxyribonuclease V / Q000378:metabolism; D005092:Exonucleases / Q000378:metabolism; D005819:Genetic Markers / Q000235:genetics; D042822:Genomic Instability; D018741:Replication Origin
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D004270:DNA, Circular; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; C066312:DnaA protein, Bacteria; D029968:Escherichia coli Proteins; D005819:Genetic Markers; C071446:RecG protein, E coli; D005092:Exonucleases; D043211:Exodeoxyribonuclease V; C506743:priA protein, E coli; D004265:DNA Helicases
references.citation: Trends Microbiol. 2008 May;16(5):238-45
references.pmid: 18406139
references.citation: BMC Mol Biol. 2012 Oct 30;13:33
references.pmid: 23110454
references.citation: Mol Microbiol. 2012 Nov;86(3):675-91
references.pmid: 22957744
references.citation: Genetics. 2010 Oct;186(2):473-92
references.pmid: 20647503
references.citation: DNA Repair (Amst). 2010 Mar 2;9(3):210-23
references.pmid: 20093100
references.citation: J Biol Chem. 2006 Aug 11;281(32):22839-46
references.pmid: 16766518
references.citation: Nat Rev Microbiol. 2007 May;5(5):343-54
references.pmid: 17435790
references.citation: Genes Dev. 2012 Jan 15;26(2):151-62
references.pmid: 22279047
references.citation: Nat Genet. 2013 Feb;45(2):214-9
references.pmid: 23313956
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6640-5
references.pmid: 10829079
references.citation: Genome Res. 2011 Aug;21(8):1388-93
references.pmid: 21555365
references.citation: Proc Natl Acad Sci U S A. 2011 Jun 28;108(26):E243-50
references.pmid: 21670292
references.citation: Nature. 2013 Mar 28;495(7442):512-5
references.pmid: 23538833
references.citation: Mol Microbiol. 2009 Nov;74(4):940-55
references.pmid: 19818016
references.citation: DNA Repair (Amst). 2010 Mar 2;9(3):202-9
references.pmid: 20097140
references.citation: Trends Biochem Sci. 2000 Apr;25(4):156-65
references.pmid: 10754547
references.citation: Cell. 2000 Mar 31;101(1):35-45
references.pmid: 10778854
references.citation: DNA Repair (Amst). 2010 Mar 2;9(3):224-36
references.pmid: 20117061
references.citation: Genes Dev. 2012 Mar 15;26(6):594-602
references.pmid: 22426535
references.citation: EMBO Rep. 2007 Feb;8(2):181-7
references.pmid: 17218953
references.citation: Microbiol Mol Biol Rev. 1997 Jun;61(2):212-38
references.pmid: 9184011
references.citation: Mol Cell. 2002 Feb;9(2):241-51
references.pmid: 11864599
references.citation: Nat Rev Genet. 2012 Feb 14;13(3):204-14
references.pmid: 22330764
references.citation: Cell. 2011 Aug 19;146(4):533-43
references.pmid: 21854980
references.citation: Mol Cell. 2010 Aug 27;39(4):595-605
references.pmid: 20797631
references.citation: Mol Microbiol. 1999 Sep;33(5):895-903
references.pmid: 10476025
references.citation: Philos Trans R Soc Lond B Biol Sci. 2011 Dec 27;366(1584):3545-53
references.pmid: 22084381
references.citation: Mol Cell. 2005 Jul 22;19(2):247-58
references.pmid: 16039593
references.citation: DNA Repair (Amst). 2007 Jul 1;6(7):981-93
references.pmid: 17400034
references.citation: Genome Res. 2012 Oct;22(10):1953-62
references.pmid: 22767388