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Fang Ba
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Ba, F.; Zhang, Y.; Wang, L.; Liu, W.; Li, J. Applications of Serine Integrases in Synthetic Biology. Encyclopedia. Available online: https://encyclopedia.pub/entry/50128 (accessed on 04 July 2024).
Ba F, Zhang Y, Wang L, Liu W, Li J. Applications of Serine Integrases in Synthetic Biology. Encyclopedia. Available at: https://encyclopedia.pub/entry/50128. Accessed July 04, 2024.
Ba, Fang, Yufei Zhang, Luyao Wang, Wan-Qiu Liu, Jian Li. "Applications of Serine Integrases in Synthetic Biology" Encyclopedia, https://encyclopedia.pub/entry/50128 (accessed July 04, 2024).
Ba, F., Zhang, Y., Wang, L., Liu, W., & Li, J. (2023, October 11). Applications of Serine Integrases in Synthetic Biology. In Encyclopedia. https://encyclopedia.pub/entry/50128
Ba, Fang, et al. "Applications of Serine Integrases in Synthetic Biology." Encyclopedia. Web. 11 October, 2023.
Applications of Serine Integrases in Synthetic Biology
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This entry is adapted from the peer-reviewed paper 10.3390/synbio1020012

Serine integrases are emerging as one of the most powerful biological tools for biotechnology. With the fast development of synthetic biology, serine integrases have been used as one of the powerful genetic tools with their unique features of site-specific, orthogonality, irreversibility, high affinity, and high efficiency. Serine integrases are widely used in diverse ways, including genome engineering, biological part and genetic circuit design, and DNA assembly. Moreover, serine integrases also advance multidisciplinary research such as chemical engineering, materials science and engineering, and biomedical engineering.

serine integrase serine recombinase synthetic biology site-specific recombination

1. Introduction

As the genetic information carrier, DNA plays the core role in leading mRNA transcription, directing protein translation, and programming cellular behaviors. The variable change of DNA sequences may reprogram life to confer desired characteristics. Over the past two decades, synthetic biology, which focuses on (re)designing and (re)constructing new biological parts, devices, systems, and organisms, has emerged with intense demands for simple, reliable, and efficient DNA manipulating tools [1]. To meet this demand, synthetic biologists have concentrated on the study of site-specific DNA-modifying enzymes that can catalyze DNA variations with precision, prediction, and high efficiency [2].
Recombinases are DNA-modifying enzymes that recognize specific double strand DNA sequences and catalyze DNA–DNA site-specific recombination. Comparing and aligning the recombinase amino acid sequences indicate two subfamilies of recombinases with distinct catalytic mechanisms: tyrosine recombinases and serine recombinases (also called serine integrases). Tyrosine recombinases cleave single-strand DNA and form covalent 3′-phosphotyrosine bonds [2][3] with the DNA backbone and rejoin DNA strands via a Holliday-Junction-like intermediate state, whereas serine integrases cleave double strand DNA and form covalent 5′-phosphoserine bonds [2][4][5] with a DNA backbone and perform as an “assembly cleavage-rotation-ligation-disassembly” process [2]. In comparison to some tyrosine recombinases with similar DNA recognition sites and reversible reactions (e.g., Cre [6], and FLP [3][7]), serine integrases can recognize and catalyze recombination events between two different and specific DNA sites (approximately 50 bp for each) called attP (attachment site in Phage) and attB (attachment site in Bacteria). Depending on the orientations of attP/attB sites, serine integrases can catalyze DNA sequences as deletion, integration, recombination, and inversion [8]. In general, serine integrase-based DNA recombination is a one-way irreversible reaction; however, this reaction can be reversed when a kind of accessory factor protein (Recombination Directionality Factor, RDF) exists [9].

2. Mechanism of Site-Specific Recombination Mediated by Serine Integrases

Serine integrases are usually discovered from bacteriophages for catalyzing their DNA integration into the recipient genome via site-specific recombination events between the attP–attB attachment site pairs [10]. When integration is finished, two new sites are formed: attL (attachment site on the left) and attR (attachment site on the right). When the host (e.g., bacteria) is converted to a lysogenic state, the prophage will evade the bacterial chromosome by expressing serine integrases with RDFs, which leads to a periodic reverse recombination event [8].
The general structural model and catalytic domains/motifs of the serine integrase subfamily have been identified clearly (Figure 1a) [11][12]. The NTD (N-Terminal catalytic Domain) contains highly conserved residues including serine (catalytic residue), tyrosine, and arginine [13]. NTD performs its function by cleavage and ligation during the recombination process (Figure 1b) [13]. The flexible αE domain plays an important role in the DNA-protein binding process [14]. RD (Recombinase Domain) mediates the attachment between attP/attB sites and the serine integrase monomer [14]. ZD (Zinc ribbon Domain) [15][16] leads to the conformationally distinct of integrase–attP and integrase–attB complexes; CC (Coiled-Coil motif) [14][17], which is embedded in the two ZDs, can assemble the two complexes of “attP-serine integrases dimer” and “attB-serine integrases dimer” to form a DNA-protein homologous tetramer [13][18]. A recently proposed structural model showed the recombination event containing six steps: (1) DNA-protein dimerization [18], (2) assembly of tetramer complex [18][19][20], (3) double strand DNA cleavage within 2 bp overhangs [8], (4) complex 180° rotation [19][21][22], (5) DNA re-ligation [19], and (6) disassembly of tetramer complex [12] (Figure 1b).
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Figure 1. Domains and proposed recombination model of serine integrases. (a) General structural domains and motifs of serine integrases. NTD: N-Terminal catalytic Domain; αE: flexible linker; RD: Recombinase Domain; ZD: Zinc ribbon Domain; CC: Coiled-Coil motif. ZD is embedded between the two ZDs; CC is divided into two antiparallel helical segments. (b) Proposed model of serine integrase-mediated recombination. First, integrase dimers specifically bind to attP or attB site depending on the ZD binding position. Second, dimer–attP and dimer–attB complexes will be automatically assembled as homologous tetramer by stabilization between CCs interaction. Third, integrase monomers cleave attP and attB sites and form 5′-phosphoserine linkages, DNA half-sites, and 3′ dinucleotide overhangs (2 bp). Then, PL-BL or PR-BR dimeric complexes will rotate 180° along the horizontal axis. After that, PL-BR and BL-PR dimeric complexes will be formed by ligation between DNA strands, called attL and attR. Finally, the CCs will be conformationally changed and form a new internal interaction along with the same DNA double strand rather than two heterologous DNA strands, which leads to disassembly and inhibits reversible exchange. (c) Proposed structural model of serine integrase-mediated reverse recombination. RDFs bind to CCs and alter the integrase–attL and integrase–attR internal interactions. The released CCs may interact with each other located on two heterologous DNA strands and reassemble again.
RDF is a small protein encoded by bacteriophages that can alter the recombination direction [23]. Some serine integrases and their paired RDFs have been characterized such as Bxb1 (RDF: gp47) [24], phiC31 (RDF: gp3) [25][26], phiBT1 (RDF: gp3) [27], A118 (RDF: Gp44) [28], and TP901-1 (RDF: orf7) [29]. When RDF exists, a possible model of reverse recombination indicates that RDF may bind to CCs to prohibit the internal dimeric DNA-protein interaction (Figure 1c) [14].

3. Orientation of att Sites

As the origin of serine integrases, bacteriophages facilitate their invasion via site-specific circular DNA integration and later convert into a lysogenic state to excise (delete) their linearized DNA from the host genome by co-existence of integrase and RDF (Figure 2a) [10]. This process inspires researchers to rearrange the orientation of attP/attB sites to utilize them for other synthetic biology and bioengineering applications. For example, when attP/attB sites are located in two different linearized DNA, the two strands will exchange partial fragments specifically to create two recombined DNA strands (Figure 2b) [30]. This strategy can also be developed as multiple linear DNA assembly in one pot [31]. In addition, when recombination occurs between two circular DNA (e.g., plasmids), these two molecules will be assembled into a merged, large circular DNA [32]. When RDF exists, the merged circular DNA can be disassembled and separated into two independent circular DNA molecules (Figure 2c). Furthermore, when attP/attB sites are oppositely located in the same DNA strand, serine integrases (with or without RDFs) enable the inversion of the internal DNA sequence (Figure 2d) [8]. In summary, depending on the orientation of attP/attB sites, serine integrases can rearrange DNA sequences as integration/deletion, recombination, assembly/disassembly, and inversion.
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Figure 2. Serine integrases with different att site orientations. Serine integrases catalyze attP and attB recombination to make attL and attR sites. When integrases and RDFs exist simultaneously, the direction will be reversed. (a) Integration mediated by serine integrases, and deletion when RDFs exist. (b) Recombination between two linear DNA strands. (c) Circular DNA assembly and disassembly. (d) Inversion of internal DNA sequence located in att sites. Red arrow: direction of internal DNA sequence.

4. Recent Achievements of Serine Integrases in Synthetic Biology

In 2012, Bonnet et al. first created a rewriteable recombinase addressable data (RAD) module, which utilized serine integrases and excisionases to invert DNA sequences (e.g., promoter) as reversible inversion [33]. This innovative design opened the next decade of emerging studies of serine integrases in synthetic biology (Figure 3). Next year, two papers reported significant designs, which were inspired by electronics engineering. Siuti et al. [34] and Bonnet et al. [35] brought Boolean logic circuits to serine integrase-based genetic logic circuit design (e.g., AND, OR, and NOT gates). Meanwhile, Bonnet et al. reported a genetic amplifier via the RNA polymerase flow by the programmable serine integrases [35]. After that, a series of serine integrase-based biological parts and genetic circuit designs were established nearly every year, for instance, genetic memory circuits [34][36][37], population-based logic circuits [38][39], state machines [40], synthetic feedback loops [41], comprehensive layered circuit systems [42][43], coding sequence manipulation [44], binary counting module [45], genetic cascades [46], “keys match locks” model [47], and cellular differentiation circuits [38][39][48].
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Figure 3. Timeline of milestones in serine integrase-associated synthetic biology.
Another serine integrase utilization is in vitro linear DNA assembly for defined purposes. In 2014, Colloms et al. first reported a strategy for constructing metabolic pathways via assembling multiple linearized DNA fragments by orthogonal serine integrases [31].

5. Serine Integrase Applications

Depending on the purposes, serine integrases can be utilized as DNA manipulation tools both in vitro and in vivo. First, serine integrases are broadly developed as diverse genome engineering tools in different hosts (e.g., bacteria [49], yeast [50], mammalian cells [51][52][53][54], animals [55][56], and plants [57][58][59][60]), and catalyze various reactions (e.g., integration and deletion) (Figure 4a). Second, serine integrases inspire the creative designs of new biological parts (Figure 4b) and the assembly of comprehensive genetic circuits (Figure 4c). Furthermore, orthogonal serine integrase systems enable in vitro assembly of either linear DNA (Figure 4d) [31] or circular DNA (Figure 4e) [47]. Both can produce large biobricks and assemble several independent modules for the designed applications, for example, the biosynthesis of carotenoid [61], erythromycin [62], and the co-expression of chromoproteins [47].
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Figure 4. Application of serine integrases in different ways. (a) The development of serine integrase-based genome engineering strategies includes exogenous DNA integration and genome sequence manipulation (e.g., deletion and inversion). (b) Designs of new biological parts with programmable serine integrases as controllers. (c) Serine integrase-based genetic circuits organize multiple biological parts to achieve more complex functions in living cells. In general, engineered circuits consist of several input signals, multilayered genetic regulators (including logic gates, amplifiers, and memory modules), and diverse output signals. Meanwhile, the host organism can be programmed into predictable states (e.g., S1–S5 means different states: state 1 to state 5). Serine integrases are represented by A and B. (d) Assembly of linear DNA fragments require the matched attP/attB sites localized on fragment ends. Orthogonal serine integrases or orthogonal 2 bp overhangs should be engineered and applied. (e) Assembly of circular DNA (e.g., plasmids) requires orthogonal attP/attB sites located in different DNA molecules. Multiple rounds of assembly can produce predicted and complicated larger plasmids.

6. Serine Integrases Accelerate the Synthetic Biology Research

In 2000, the innovation of the genetic toggle switch [63] and repressilator [64] represented the beginning of synthetic biology research. After more than 10 years, the first serine integrase-based genetic converter was designed in 2012 [33]. After that, serine integrase accelerated synthetic biology over the next decade with many remarkable milestones (Figure 3). The emerged designs covered multidisciplinary fields. Figure 5 summarizes the published papers and propose a scheme within the “design-build-test-learn” cycle, including three modules as “input-process-output” genetic workflow, and three independent dimensions as host organism, external carrier, and enabling technology.
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Figure 5. Schematic overview of serine integrases-based synthetic biology. TXTL: transcription-translation.
Input signals enable cells to sense and respond the external environment for altering their metabolism and behavior (Figure 5, middle left). Up to now, the main inducers for serine integrase expression are chemical molecules [40] such as arabinose, anhydrotetracycline, 2,4-diacetylphloroglucinol (DAPG), and some metal ions like cadmium [65] with strictly regulated inducible circuits to prohibit leakage. 
The signal process occurs when the recipient receives the input signals and converts them into genetic information (Figure 5, middle). Unique properties of serine integrase like site-specific, orthogonality, predictable, and high efficiency, empower it as a genetic information processor. The simple Boolean logic gates could be designed as single-layered circuits (e.g, binary counting module [45], and “keys match locks” module [47]), and also could be assembled as multilayered networks [66] such as amplifier [35], allocator [66], genetic cascades [46], feedback loops [41], and modified genetic barcodes [55].
Depending on genetic information processing, the host can export diverse outputs (Figure 5, middle right). The general output signal is fluorescence, including fluorescent proteins and luciferases. Additionally, engineered microorganisms could produce amyloid fibers [67] and natural products [62][68][69] as output signals. Furthermore, the processed signals enable bacteria to reprogram their phenotypes.
As previously reported, serine integrases were active in a wide range of hosts, including not only prokaryotes (E. coli [49], Pseudomonas [70], Rhodococcus [71], and other non-model bacteria [72]), but also eukaryotes (Saccharomyces cerevisiae [50] and mammalian cell lines [51][52][53][54][73][74]), animals (Drosophila [55] and mouse [56]), and plants (tobacco [58][59] and Arabidopsis [57][60]) (Figure 5, top). 

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Subjects: Biotechnology & Applied Microbiology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Fang Ba
,
Yufei Zhang
,
Luyao Wang
,
Wan-Qiu Liu
,
Jian Li
View Times: 343
Revisions: 2 times (View History)
Update Date: 13 Oct 2023
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