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How a virus associated with the virulence of the cholera bacterium hijacks a bacterial-specific recombination machinery

Many mobile elements use the Xer machinery of bacteria to integrate into the dif site of one of the chromosomes of their bacterial host. Integrative mobile elements using Xer (IMEX) are often associated with pathogenicity. The evolutionary history of the cholera agent, Vibrio cholerae, is a remarkable example of that point.

A major difference between bacteria and eukaryotes is intrinsic to the structure of their chromosomes: they are linear in eukaryotes and circular in bacteria. DNA circularity can result in the formation of chromosome dimers, which physically impede the segregation of genetic information at cell division. However, bacteria have evolved a highly conserved chromosomally-encoded recombination (Xer) machinery to resolve chromosome dimers by the addition of crossovers at a specific unique site of their circular chromosomes, dif.
The Xer machinery belongs to the family of tyrosine recombinases. It is very similar to Cre, the resolvase of phage P1, whose action mechanism has been thoroughly characterised at the atomic resolution. However, several features of the Xer machinery differentiate it from Cre and most other tyrosine recombinases. In particular, Xer is under the control of a large integral membrane protein, FtsK, which limits its action to the time of cell division and ensures fully efficient recombination between any two dif sites carried on the same DNA molecule.

Numerous mobile elements exploit Xer to integrate into the dif site of one of their host chromosomes. Integrative Mobile Elements exploiting Xer (IMEX) are often associated to pathogenicity. A salient example is provided by the evolutionary history of the agent of the cholera, Vibrio cholerae.
V. cholerae is found in briny waters all over the world. However, most strains are not pathogenic or only cause local outbreaks of gastroenteritis. The diarrhoea that is responsible for the epidemic propagation and high death rate associated with cholera is due to a toxin that is encoded in the genome of an IMEX, the cholera toxin phage (CTXΦ). Interactions between CTXΦ and several other IMEX participate in the constant and rapid emergence of new cholera epidemic strains. Foremost among those is the toxin-linked cryptic satellite phage, TLCΦ, whose integration is a prerequisite for CTXΦ integration. TLCΦ carries a poor binding site for the Xer machinery, which prevents its excision by FtsK-dependent recombination events. However, it remained to be understood how this site could be exploited for integration.

The Barre group have shown that TLCΦ encodes for its own Xer activation factor, XafT, which permits to bypass the requirement for FtsK for Xer recombination. They further shown that the genomes of different human, animal, and plant bacterial pathogens harbor IMEXs encoding for XafT homologs, indicating that the TLCΦ-integration strategy is widely employed. Their results open up new possibilities to study the mechanism of activation of the Xer machinery at the atomic resolution and could help design of drugs that would reverse the pathogenicity of some bacteria by promoting the instability of IMEX-associated toxin or other virulence factors.

Reference :
The TLCΦ satellite phage harbors a Xer recombination activation factor
C. Midonet, S. Miele, E. Paly, R. Guérois and F-X. Barre
Proc. Natl. Acad. Sci. U.S.A., 2019, DOI: 10.1073/pnas.1902905116

Contact: François-Xavier Barre

by Communication - published on , updated on