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To Cut or Not to Cut-The Bacterial Dilemma!

Some bacteria possess an interesting ability of incorporating a new piece of DNA from the outside.This new DNA might come from its surroundings, other bacteria or even invading virus and might help in fostering genomic diversity. In fact, scientists now believe that this phenomenonis much more common than previously thought. However, incorporating a viral DNA may be harmful where the viruses utilize every opportunity to sneak into a bacterium and, hijack its machinery to replicate the viral DNA. Hence, to protect themselves, bacteria have evolved a mechanism called restriction modification system. And yet, it could work for the advantage of the bacterium sometimes to restrain this system and usher in new foreign DNA that might contribute to its own genomic diversity.

Restriction modification systems contain two kinds of enzymes - restriction enzymes which recognize foreign DNA and cut them and modification enzymes (methyltransferases), which methylate DNA and protect them from restriction enzymes. Cutting a foreign DNA destroys it functionally since the fragments will be chewed up and the nucleotides will be reused. However if a DNA is methylated at specific places, the restriction enzymes will not cut it. This methylation process is necessary for the bacterium to protect its own DNA from its own restriction enzymes!

Helicobacter pylori- is a bacterium that has been proven to be the cause of gastric inflammation and can lead to gastric cancer. The genome (set of all genes) of H.pylori is very diverse and this diversity helps it to adapt to inhabiting one of the most inhospitable habitats- our acid secreting stomach.

One way the bacterium achieves its genomic diversity is by welcoming foreign DNA much more readily than other bacterium. For that, it has to block its restriction enzymes from acting unduly on any foreign DNA entering the cell. A protein known as DprA (DNA Processing protein A) has been known to protect any single stranded DNA entering a cell. Dr. Gajendradhar Dwivedi, a former researcher at the Department of Biochemistry, Indian Institute of Science, Bangalore, has found that DprA in H.pylori binds and protects not only single stranded DNA, but also double stranded DNA which is the form of DNA found naturally. He has also found that DprA actively interacts with methyltransferases and facilitates the methylation of incoming foreign DNA, adding another layer of protection. It is like welcoming a foreign guest by providing a high level of security. This mechanism helps the bacterium to invite foreign DNA and incorporate it with its own genome, thus increasing its genomic diversity and helping it to adapt better.

Methyltransferases, the enzyme that protects a DNA through modification, need a methyl group donor for methylating DNA, which they get from another molecule called SAM (S- adenosyl methionine). methyltransferases therefore have to bind to both SAM and DNA. Some first bind to SAM and then to DNA, while some do it the other way. Mr. Yedu Prasad, a researcher at the same lab, works on the determination of the order of binding of - a type III methyltransferase. He observed that it binds SAM first and then DNA.

Does the order in which it binds matter? “Yes, because enzymes that bind DNA first are known to be more processive” says Mr. Prasad. A processive enzyme remains with the substrate for longer periods and hence is more efficient in their enzymatic activity – in this case, the methylation of the DNA.

The concentration of SAM is also important for the fact that it could eventually decide whether a given DNA in the cell gets cut or protected! If the SAM concentration is more, the DNA might preferentially get methylated first and therefore protected before it gets cut. This again adds to the genomic diversity of the bacterium. Interestingly, with some specific methyltransferases, the relative concentration of SAM is dynamically altered as the situation demands. This means that the bacterium either can choose to cut a foreign DNA entering a cell or protect it through methylation by actively altering the concentration of SAM inside the cell.

Given the prevalence of H.pylori (- more than 80% of the Indian population suspected to be carriers) as a causative agent of gastritis and its role in gastric cancer, it is important that we know about the defenses and versatility of this bacterium. These findings take us nearer to achieving this goal.

Contact Information:

Dr. Gajendradhar Dwivedi can be reached at gajendradhar85@gmail.com

Mr. Yedu Prasad is a research scholar in Prof. D. N. Rao’s Lab, Department of Biochemistry, Indian Institute of Science, Bangalore. He can be reached at yeduprasad108@gmail.com