Addicted to DNA…

BACTERIA can find themselves in the rather undesirable position of being addicted to parasites. The parasites in question are not of the blood-sucking sort however, but rather of the gene-sucking sort.

In nature there are numerous genetic entities, various forms of DNA, that parasitise bacteria:

• bacteriophages (viruses that infect only bacteria),
• plasmids (usually a circular strand of DNA that exists separately to the bacteria’s chromosome),
• transposons (a unit that consists of a collection of genes that inserts itself into the host’s chromosome, but can cut itself free and reinsert itself elsewhere on the chromosome) and conjugative transposons (also capable of transferring themselves from cell to cell between bacteria),
• genomic islands (again, a collection of genes that usually encode particular functions – disease-causing factors or antibiotic resistance – that have arrived from another organism and have become fixed in the chromosome).

We also have integrative conjugative elements (ICEs) that, like conjugative transposons, insert themselves into the host’s chromosome where they are replicated along with the host’s DNA, but then periodically (often under stress) cut themselves free and mail a copy off to another host cell.

Transfer of any of the above genetic entities can result in a bacterial cell acquiring new and desirable traits as such as the ability to consume new food sources, or resist antibiotics, or be more invasive. These traits have been picked up via the many occasions that these elements have jumped into and out of bacterial chromosomes, taking bits of those chromosomes with them.

The transfer of new traits by these genetic entities is referred to as Horizontal Gene Transfer (HGT), which is a term that is perhaps easier to understand if we consider that sexual reproduction, the process by which your parents produced you, is a form of vertical gene transfer; so too is the division of a single bacterial cell to produce a copy of itself and a ‘daughter’ cell. By comparison, horizontal gene transfer might be likened to you reaching out to touch your cousin and acquiring his or her ginger hair and freckles.

The thing that unites these genetic elements is that, being parasites, they need the host cell in order to produce more of themselves. Sometimes these elements don’t provide anything useful to the cell, sometimes they’re more of a burden, but some of these genetic parasites have evolved ways to ensure that the cell doesn’t toss them aside.

One such way is by by employing a Toxin-Antitoxin (TA) system. These systems have been well characterised in plasmids that exist in a variety of different bacteria, but the example I’m using today comes from a rather large ICE called ‘SXT’, which is found in Vibrio cholera, the bacteria that causes Cholera. Such genetic elements are of concern in V. cholera as another such genetic parasite, a bacteriophage called CTX (which also inserts itself into the chromosome of the bacteria), is responsible for carrying the potent cholera toxin gene, thus converting a relatively harmless bacteria into a killer of millions worldwide. For its own sins, SXT encodes resistance to several antibiotics, and represents a means by which the rapid treatment of cholera can be impeded by acquired antibiotic resistance.

But what is a toxin-antitoxin system? The schematic on the left, from a accompanying paper in the same issue of PLos Genetics, essentially shows that in the presence of a TA system, cells that lose the genetic parasite encoding the TA die, a phenomenon called post segregational killing (PSK).

In a paper from the laboratory of Matt Waldor (Tufts University, Boston), Rachel Wozniak has identified a toxin-antitoxin system in SXT, the first time that a TA system has been shown to promote ICE maintenance. SXT encodes a toxin gene (mosT) producing a toxin that impairs cell growth, it also encodes an antitoxin that neutralises the effect of the toxin (mosA). Thus, whilst both mosA and mosT continue to co-exist, all is well.

However, if SXT is ever to cut itself free and mail a copy of itself to another cell, which it may do when its current cell becomes stressed, it needs to free itself from the chromosome and form a separate circular strand of DNA. At this point, because it cannot produce more of itself whilst on its own, it could be lost when the cell divides.

In other TA systems, the toxin molecule is relatively stable and long-lived, whereas the antitoxin is unstable, therefore relatively short-lived. So, in the absence of a fresh supply of antitoxin, there is sufficient toxin remaining to cause damage to the cell. This pairing of toxin and antitoxin is sometimes referred to as an addiction module, with cells becoming dependent on the continued presence of genetic element as a result.

For this reason, despite SXT cutting itself free of the host chromosome in more than 1 in 100 cells, and so becoming vulnerable to loss, it is in fact only lost in 1 in 100 million cells.

That’s quite an addiction.

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Wozniak, R., & Waldor, M. (2009). A Toxin–Antitoxin System Promotes the Maintenance of an Integrative Conjugative Element PLoS Genetics, 5 (3) DOI: 10.1371/journal.pgen.1000439

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