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Possibly The Most Ignored Reality On Nintedanib

During integration Int drives recombination between specific attachment sites on the phage and host chromosomes called attP and attB respectively. The outcome is an integrated phage genome flanked by two new attachment sites, attL and attR. Under inducing conditions, when the phage re-enters the lytic cycle, the phage genome is excised via integrase-mediated recombination between attL and attR to regenerate attP and attB. Thus integration and excision of the phage genome needs to be tightly regulated to prevent integration CDK inhibitor during the lytic cycle, to permit integration in a cell entering lysogeny

and to enable excision during induction. As integrase is required for both integration and excision, a phage-encoded accessory protein (a recombination directionality factor, RDF or Xis) is normally expressed that controls the activity of integrase. In the absence of an RDF, all phage integrases described to date are unidirectional, mediating only integration. In the presence of the RDF the directionality of integrase is switched so that excision is activated and, normally, integration is inhibited (Azaro and Landy, 2002). Phage integrases fall into one of two families of recombinases, the tyrosine recombinases that include phage �� integrase, �� Int, or the serine integrases including those from the Streptomyces phage ��C31 and mycobacteriophage

Bxb1 (Azaro and Landy, 2002; Kim et?al., 2003; Smith et?al., 2010). The �� Int family and the serine integrases are evolutionarily and mechanistically distinct. The �� Int family generally have a large attP site that contains an array of binding sites for Int and accessory proteins, IHF, Fis and Xis. The accessory proteins guide the path of the DNA in the assembly of the synaptic complex, an important early stage in recombination when the attachment sites are brought together in close proximity before catalysis. �� Xis is a DNA binding and bending

protein that controls the directionality of �� Int by enabling the formation of the excision synapse and preventing the formation of the integration synapse (Azaro and Landy, 2002). The �� Int paradigm does not hold for serine integrases (Ghosh et?al., 2006; Smith et?al., 2010). The serine integrases use small (<?50?bp) attP and attB sites for integration (Smith and Thorpe, 2002). The ��C31 attP and attB sequences share approximately 30% sequence identity and both contain imperfect inverted repeats. The attL and attR sites are therefore hybrids containing one half site from attP and a half site from attB. The attachment sites are bound by dimers of Int, with each subunit binding to one half site (Thorpe et?al., 2000; Ghosh et?al., 2005). When Int is bound to specific pairs of sites (such as attP and attB for integration) the bound dimers bring the two sites together in a synaptic complex, probably through formation of an Int tetramer (Ghosh et?al., 2005; Grindley et?al., 2006).</div>
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