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Review
. 2016 Aug 19;7(8):52.
doi: 10.3390/genes7080052.

Remodeling and Control of Homologous Recombination by DNA Helicases and Translocases that Target Recombinases and Synapsis

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Review

Remodeling and Control of Homologous Recombination by DNA Helicases and Translocases that Target Recombinases and Synapsis

Sarah J Northall et al. Genes (Basel). .

Abstract

Recombinase enzymes catalyse invasion of single-stranded DNA (ssDNA) into homologous duplex DNA forming "Displacement loops" (D-loops), a process called synapsis. This triggers homologous recombination (HR), which can follow several possible paths to underpin DNA repair and restart of blocked and collapsed DNA replication forks. Therefore, synapsis can be a checkpoint for controlling whether or not, how far, and by which pathway, HR proceeds to overcome an obstacle or break in a replication fork. Synapsis can be antagonized by limiting access of a recombinase to ssDNA and by dissociation of D-loops or heteroduplex formed by synapsis. Antagonists include DNA helicases and translocases that are identifiable in eukaryotes, bacteria and archaea, and which target synaptic and pre-synaptic DNA structures thereby controlling HR at early stages. Here we survey these events with emphasis on enabling DNA replication to be resumed from sites of blockage or collapse. We also note how knowledge of anti-recombination activities could be useful to improve efficiency of CRISPR-based genome editing.

Keywords: Hel308; helicase; homologous recombination; synapsis.

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Figures

Figure 1
Figure 1
(A) Replication restart by homologous recombination and actions that control it at pre-synapsis or synapsis. (a) Several possible branched DNA structures can arise when replication forks are compromised as a result of chemical damage or protein bound DNA complexes. These include ssDNA gaps and DNA strand breaks, indicated by the red paint-splash. Exposed single stranded DNA (ssDNA) within partial duplexes is coated by binding proteins (e.g., SSB and RPA); (b) RPA/SSB can be removed from ssDNA by DNA helicases following replication fork stalling, to facilitate loading of recombinase monomers onto ssDNA as a nucleoprotein filament (NPF); (c) A recombinase NPF catalyses strand invasion into homologous duplex, aided by mediator proteins that include Rad51 paralogues, displacing the complementary strand creating a D-loop (synapsis); (d) The NPF may be disrupted by DNA translocases via physical displacement of the NPF by ATP dependent protein translocation or, by physical interaction between DNA translocases and the NPF monomers that activates intrinsic ATPase activity within the NPF causing filament disassembly. Various helicases have roles here, as detailed in the text and listed in the figure; (e) Following synapsis, the recombinase can be removed from heteroduplex DNA, for example by Hel308/ HelQ proteins; (f) Extension of 3′ OH invading strand by replicative DNA polymerases illustrates the interplay between nascent DNA replication and the onset of homologous recombination (HR). This can lead to Holliday junction formation and full homologous recombination toward crossover or non-crossover products (see Figure 1C); (g) Unwinding of the invading strand in D-loops occurs by DNA helicases such as RecQ or RTEL1 to allow for SDSA or break induced replication (BIR) that form non-crossover products; (B). Synthesis dependent strand annealing after synapsis. (a) Synapsis leads to D-loop formation in which an available 3′ OH end of the invading strand can be extended by polymerases (b); (c) The extended DNA strand arising from synapsis and replication can be displaced from the D-loop thereby preventing end capture and the later stages of HR. Nascent DNA is re-annealed, extended further (if necessary) and ligated to its original strand; (C) Crossover versus Non-crossover events in homologous recombination. Pathways of HR repair DNA damage in ways that can lead to different genetic outcomes in terms of genome stability. Non-crossover is the preferred outcome to maintain genetic status quo and occurs preferentially through BIR, synthesis dependent strand annealing (SDSA) and controlled HR pathways where sites flanking repaired regions remain in place. Crossover can occur following resolution of Holliday junctions where reciprocal exchange of sites flanking repaired regions takes place and can lead to chromosomal rearrangements. Gene conversion following copying of genetic information from intact homologous DNA can occur in addition during crossover and non-crossover events.
Figure 2
Figure 2
Direct Replication Restart. (A) PriA * recognizes branched DNA structures arising at stalled replication forks. It remodels forks to present substrates for binding by replicative helicase loading proteins PriB and PriC; (B) Recruitment of the replicative helicase DnaB for loading onto the lagging strand template allows replication to be re-activated; (C). * Protein nomenclature here refers to E. coli.

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