2019
DOI: 10.1073/pnas.1914485116
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A gatekeeping function of the replicative polymerase controls pathway choice in the resolution of lesion-stalled replisomes

Abstract: DNA lesions stall the replisome and proper resolution of these obstructions is critical for genome stability. Replisomes can directly replicate past a lesion by error-prone translesion synthesis. Alternatively, replisomes can reprime DNA synthesis downstream of the lesion, creating a single-stranded DNA gap that is repaired primarily in an error-free, homology-directed manner. Here we demonstrate how structural changes within theEscherichia colireplisome determine the resolution pathway of lesion-stalled repli… Show more

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Cited by 19 publications
(34 citation statements)
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“…Given the requirement of the β-clamp for activity of specialized polymerases and evidence for damage-dependent changes in localization of replisome components such as SSB in actively replicating E. coli (Chang et al, 2019; Henrikus et al, 2018; Soubry et al, 2019; Thrall et al, 2017), we generated fluorescent fusions to the Caulobacter β-clamp (DnaN), component of the clamp loader complex (HolB), the replicative polymerase PolIII (DnaE), and single-strand binding protein (SSB), (using previously described approaches in Caulobacter (Aakre et al, 2013; Collier & Shapiro, 2009) ; and materials and methods) in order to visualize them in non-replicating swarmers. These fusions did not perturb the function of the proteins as cells displayed wild type growth dynamics in steady-state conditions (Figure S1A and S1B ‘control’).…”
Section: Resultsmentioning
confidence: 99%
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“…Given the requirement of the β-clamp for activity of specialized polymerases and evidence for damage-dependent changes in localization of replisome components such as SSB in actively replicating E. coli (Chang et al, 2019; Henrikus et al, 2018; Soubry et al, 2019; Thrall et al, 2017), we generated fluorescent fusions to the Caulobacter β-clamp (DnaN), component of the clamp loader complex (HolB), the replicative polymerase PolIII (DnaE), and single-strand binding protein (SSB), (using previously described approaches in Caulobacter (Aakre et al, 2013; Collier & Shapiro, 2009) ; and materials and methods) in order to visualize them in non-replicating swarmers. These fusions did not perturb the function of the proteins as cells displayed wild type growth dynamics in steady-state conditions (Figure S1A and S1B ‘control’).…”
Section: Resultsmentioning
confidence: 99%
“…DNA lesion repair and tolerance has been well-studied in a replication-centric paradigm (Gabbai et al, 2014; Indiani et al, 2005; Marians, 2018). Characterization of error-prone polymerases in E. coli has informed us about mechanisms of tolerance that could occur at the replication fork or behind it, in gaps generated due to replisome skipping over the lesion, followed by repriming downstream of it (Chang et al, 2019; Gabbai et al, 2014; Indiani et al, 2005). However, DNA damage is a universal event that can occur across all stages of the cell cycle, including in non-replicating conditions.…”
Section: Discussionmentioning
confidence: 99%
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“…Since error-prone polymerases can synthesize DNA and their activity is mediated by interaction with the β-clamp of the replisome ( Bunting et al, 2003 ; Chang et al, 2019 ; Fujii and Fuchs, 2004 ; Thrall et al, 2017 ; Wagner et al, 2009 ; Warner et al, 2010 ), action of these polymerases has mostly been studied in the context of replicating cells, as a mechanism that facilitates continued DNA synthesis by acting at or behind the replication fork ( Chang et al, 2019 ; Chang et al, 2020 ; Indiani et al, 2005 ; Jeiranian et al, 2013 ; Marians, 2018 ). In addition to replication-associated lesion tolerance, some studies have proposed the possibility of error-prone synthesis in a manner that is replication-independent ( Janel-Bintz et al, 2017 ; Kozmin and Jinks-Robertson, 2013 ).…”
Section: Introductionmentioning
confidence: 99%
“…However, the high affinity of replicative polymerase for primer–template (P/T) junctions may be altered when replisomes stall. The stalling process may induce conformational changes that increase the chances for TLS Pols to gain access to the stalled template through interaction with the processivity clamp, as recently suggested in vitro by an elegant work in Escherichia coli [ 28 ]. This work is, however, in contrast with a previous report using a single-molecule assay, showing that TLS Pol competition with replicative polymerase is instead concentration-dependent and is not affected by the lesion recognition [ 29 ].…”
Section: The Crucial Role Of Tls To Tolerate Structural Impediments During Dna Replicationmentioning
confidence: 99%