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In many species of bacteria there are peculiar hybrid structures called retrons which are half RNA and half single stranded DNA. Since their discovery some 35 years ago, researchers have learned to use backons to produce single strands of DNA in the laboratory, but no one knew what their function was in bacteria, despite much research on the subject. In an article published today in Cell, a team at the Weizmann Institute of Science reports that they have solved the long-standing mystery: retrons are immune “guards” that ensure the survival of the bacterial colony when infected with the virus. In addition to uncovering a new strategy used by bacteria to protect themselves from viral infection, strikingly similar to that employed by plant immune systems, the research revealed many new backstones that could, in the future, be added to the genome editing toolkit.
The study, conducted in the laboratory of Prof. Rotem Sorek of the Institute’s Department of Molecular Genetics, was led by Adi Millman, Dr. Aude Bernheim and Avigail Stokar-Avihail in his laboratory. Sorek and his team haven’t set out to solve the retron mystery; they were looking for new elements of the bacterial immune system, particularly elements that help bacteria fend off viral infections. Their search was made easier by the recent discovery that the genes of the bacteria’s immune system tend to cluster in the genome within so-called defense islands. When they discovered the retron’s unique signature within a bacterial defense island, the team set out to investigate further.
Their initial research showed that this retron was definitely involved in protecting bacteria against viruses known as phages that specialize in infecting bacteria. While the researchers took a closer look at additional backons located near known defense genes, they found that backons were always linked – physically and functionally – to another gene. When the accompanying gene or retron was mutated, the bacteria were less successful in fighting the phage infection.
The researchers therefore decided to look for other complexes of this type in the defense islands. Eventually, they identified around 5,000 retrons, many of them new, on several defense islands of numerous bacterial species.
To test whether these retrons generally function as immune mechanisms, the researchers transplanted many retrons, one by one, into laboratory bacterial cells without retrons. As they suspected, in large numbers of these cells they found backs that protected the bacteria from phage infection.
How do retrons do it? By focusing on a particular type of retron and tracking its actions in the face of phage infection, the research team found that its function is to induce the infected cell to commit suicide. Cell suicide, once thought to belong exclusively to multicellular organisms, is an ultimate means of aborting a widespread infection if the suicide mechanism works fast enough to kill the cell before the virus finishes making copies of itself and spreading. to other cells.
The retron does not need to be able to identify all possible inhibitors, just to have a check on the functioning of a particular immune complex
Further investigation showed that the retrons do not perceive the phage invasion itself, but rather keep an eye on another part of the immune system known as RecBCD, which is one of the bacterium’s first lines of defense. If it realizes that the phage has tampered with the cell’s RecBCD, the retron activates its program through linked second genes to kill the infected cell and protect the rest of the colony.
“It’s a smart strategy and we’ve found that it works similar to a protective mechanism employed in plant cells,” says Sorek. “Just like viruses that infect plants, phages are equipped with a variety of inhibitors to block assorted parts of the cellular immune response. The retron, as a guard mechanism known to exist in plants, does not need to be able to identify all possible inhibitors, just to have a check on the functioning of a particular immune complex. Infected plant cells apply this method of “abortive infection”, killing a small region of a leaf or root in an attempt to save the plant itself. Since most bacteria live in colonies, this same strategy can promote group survival, even at the expense of individual members. “
Retrons are so useful to biotechnology because they start with a piece of RNA, which is the blueprint for the synthesis of the DNA strand. This pattern in the retron sequence can be swapped for any desired DNA sequence and used, sometimes in combination with another tool borrowed from the bacterial immune toolkit – CRISPR – to manipulate genes in various ways. Sorek and his team believe that within the diverse list of retrons they have identified there may be more than a few that may provide better models for specific genetic modification needs.
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