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Chapter 3 : The Serine Recombinases

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Abstract:

The term site-specific recombination encompasses a group of biological processes that, unlike homologous recombination, promote rearrangements of DNA by breaking and rejoining strands at precisely defined sequence positions. In a canonical site-specific recombination event, two discrete sites (sequences of DNA, typically a few tens of base pairs long) are broken, and the ends are reciprocally exchanged and rejoined, resulting in recombinant products ( Fig. 1 ). Site-specific recombination does not require extensive sequence homology; the sites are identified and brought together by protein–DNA and protein–protein interactions involving specialized recombinase proteins, unlike homologous recombination where DNA–DNA interactions define the loci of strand exchange. “Conservative” site-specific recombination systems form recombinants without any requirement for DNA synthesis or high-energy cofactors. Some other biological processes such as transposition are sometimes categorized with site-specific recombination because of common features including cleavage and rejoining of DNA strands at precise positions defined by protein–DNA interactions, but these processes may require DNA synthesis and/or ligase-mediated rejoining of DNA strands. The systems discussed in this chapter conform to the strict “conservative” definition. General aspects of site-specific recombination have been reviewed elsewhere ( ).

Citation: Stark W. 2015. The Serine Recombinases, p 73-89. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0046-2014
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Figures

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Figure 1

Site-specific recombination. Two sites (pointed boxes) in double-helical DNA (shown as double lines) are recognized by a recombinase protein (not shown), and then cut and rejoined to form recombinants.

Citation: Stark W. 2015. The Serine Recombinases, p 73-89. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0046-2014
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Figure 2

Site-specific recombination outcomes. (a) Recombination between two sites in separate linear DNA molecules results in two linear recombinant products. Usually, the sites have a polarity (indicated by the pointed boxes) such that the lower pathway (red arrow) is forbidden. (b) Recombination between two sites in separate DNA molecules, when one or both of the molecules is circular, results in a single product molecule containing two sites in direct repeat. This is called integration or fusion. The “reverse” reaction splits a molecule containing two sites into two product molecules, one or both of which are circular. This is called resolution, excision, or deletion (depending on the biological context). (c) Recombination between two sites in inverted repeat in a DNA molecule inverts the orientation of one segment of DNA relative to the other. This is called inversion.

Citation: Stark W. 2015. The Serine Recombinases, p 73-89. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0046-2014
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Figure 3

Recombination sites. (a) A typical recombination site. The crossover site, where strand exchange takes place (at the position marked by the staggered red line), binds a recombinase dimer and typically has partial dyad symmetry (indicated by the blue arrows). “Accessory sites,” which may be adjacent on one side of the crossover site (as shown), on both sides or more distant, may bind additional recombinase subunits or other proteins, or may make looping interactions with recombinase bound at the crossover site. (b) Example of a real crossover site (, a site acted upon by Hin recombinase). The colors and symbols are as in part (a). Hin, like all serine recombinases characterized to date, cuts the DNA at the center of the crossover site with a 2 bp “stagger” as shown.

Citation: Stark W. 2015. The Serine Recombinases, p 73-89. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0046-2014
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Figure 4

The serine recombinase strand-exchange mechanism. A synaptic complex of two crossover sites bridged by a recombinase tetramer (yellow ovals) is shown. The four subunits are spaced out, so that the catalytic steps can be seen clearly. The catalytic serine residues are indicated by S-OH. The scissile phosphodiesters are represented as circled Ps, and in the first and last panels the 2-bp overlap sequence is indicated by vertical lines. For further details, see text.

Citation: Stark W. 2015. The Serine Recombinases, p 73-89. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0046-2014
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Figure 5

Domain structures of serine recombinases ( ). The SR (catalytic) domain (shown in pink; typically ∼150 amino acids) is common to all serine recombinases and contains the active site (red star). Small serine recombinases (including resolvases and invertases) have a helix–turn–helix DNA-binding domain (blue; ∼40 amino acids) at the C terminus. Some related recombinases such as ISXc5 resolvase have additional C-terminal domains (orange) of unknown function. Serine transposases have a similar helix–turn–helix domain at the N terminus. Large serine recombinases have multiple domains at the C terminus of the SR domain ( ).

Citation: Stark W. 2015. The Serine Recombinases, p 73-89. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0046-2014
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Figure 6

Crystal structures of γδ resolvase–NA complexes. (a) Wild-type γδ resolvase dimer bound to crossover-site DNA (PDB 1GDT; 40). The subunits are in cartoon representation (green and orange). The active site serine residues (α carbons) are indicated by magenta spheres. (b) Activated mutant γδ resolvase tetramer in a cleaved-DNA synaptic intermediate (PDB 1ZR4; 41). The resolvase is rendered as in (a). The active-site serines are covalently linked to DNA ends (see Fig. 4 ); only two are visible. This view emphasizes the flat interface (marked by a dashed red line) between “rotating pairs” of resolvase subunits. The red arrows indicate positions of double-strand breaks in the DNA. The structure corresponds to the intermediates cartooned in the two central panels of Fig. 4 .

Citation: Stark W. 2015. The Serine Recombinases, p 73-89. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0046-2014
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Figure 7

Topologically selective recombination by Tn/γδ resolvase. (a) The reaction pathway of resolvase (lower row) is contrasted with that of a non-selective recombinase (upper row). Random collision of sites results in products with a variety of topologies (a 6-noded catenane is shown as an example here). Selective synapsis by resolvase results in a product with a specific topology (2-noded catenane). (b) Architecture of the synapse. The Tn/γδ site is diagrammed on the left. On the right, the arrangement of DNA in the synapse is shown. The catalytic tetramer bound to the crossover sites (the “catalytic module”) is represented as an orange oval, and the eight resolvase subunits bound at the accessory sites (the “regulatory module”) are collectively represented by the pink oval. Chapter 10, this volume, gives more details on the structures of this and other synaptic complexes.

Citation: Stark W. 2015. The Serine Recombinases, p 73-89. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0046-2014
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Figure 8

Subunit rotation mechanism of resolvase. (a) Topologies of first round and “iteration products” observed by Cozzarelli’s group ( ). The upper part shows the products predicted by a rotation mechanism in a resolvase synapse with topology as shown in Fig. 7 . The lower panels show the simplified topologies of these products. “Mismatched” substrates (see text) form only the nonrecombinant knot products, starting with the 4-noded knot. (b). Cartoon illustrating the proposed subunit rotation mechanism. DNA is represented as ribbons and recombinase subunits as ovals. The crystal structure of a proposed intermediate in subunit rotation is shown in Fig. 6b .

Citation: Stark W. 2015. The Serine Recombinases, p 73-89. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0046-2014
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Figure 9

Cartoon of proposed inversion synaptic complex. An invertase tetramer bridging the two crossover sites is shown as an orange oval, and contacts the enhancer DNA (brown) and a FIS dimer bound there (pink). The DNA in the complex is intertwined as shown. Supercoiled loops of DNA outside the complex are shown as dashed lines.

Citation: Stark W. 2015. The Serine Recombinases, p 73-89. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0046-2014
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Figure 10

Recombination by serine integrases. In nature, integrase promotes recombination between a crossover site, , in the circular bacteriophage DNA and a different crossover site, , in the host bacterial genome (indicated by a squiggly line). Integrase alone does not promote any reaction between the product sites and . However, the presence of a bacteriophage-encoded recombination directionality factor (RDF) protein alters the properties of integrase so that it preferentially promotes × recombination (red arrow). See text for further details.

Citation: Stark W. 2015. The Serine Recombinases, p 73-89. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0046-2014
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Tables

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Table 1

Structural data for serine recombinases

Citation: Stark W. 2015. The Serine Recombinases, p 73-89. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0046-2014

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