Nav: Home

Deciphering potent DNA toxin's secrets

August 02, 2017

One of the most potent toxins known acts by welding the two strands of the famous double helix together in a unique fashion which foils the standard repair mechanisms cells use to protect their DNA.

A team of Vanderbilt University researchers have worked out the molecular details that explain how this bacterial toxin -- yatakemycin (YTM) -- prevents DNA replication. Their results, described in a paper published online July 24 by Nature Chemical Biology, explain YTM's extraordinary toxicity and could be used to fine-tune the compound's impressive antimicrobial and antifungal properties.

YTM is produced by some members of the Streptomyces family of soil bacteria to kill competing strains of bacteria. It belongs to a class of bacterial compounds that are currently being tested for cancer chemotherapy because their toxicity is extremely effective against tumor cells.

"In the past, we have thought about DNA repair in terms of protecting DNA against different kinds of chemical insults," said Professor of Biological Sciences Brandt Eichman. "Now, toxins like YTM are forcing us to consider their role as part of the ongoing chemical warfare that exists among bacteria, which can have important side effects on human health."

Cells have developed several basic types of DNA repair, including base excision repair (BER) and nucleotide excision repair (NER). BER generally fixes small lesions and NER removes large, bulky lesions.

A number of DNA toxins create bulky lesions that destabilize the double helix. However, some of the most toxic lesions bond to both strands of DNA, thereby preventing the cell's elaborate replication machinery from separating the DNA strands so they can be copied. Normally, this distorts the DNA's structure, which allows NER enzymes to locate the lesion and excise it.

"YTM is different," said postdoctoral fellow Elwood Mullins. "Instead of attaching to DNA with multiple strong covalent bonds, it forms a single covalent bond and a large number of weaker, polar interactions. As a result, it stabilizes the DNA instead of destabilizing it, and it does so without distorting the DNA structure so NER enzymes can't find it."

"We were shocked by how much it stabilizes DNA," Eichman added. "Normally, the DNA strands that we used in our experiments separate when they are heated to about 40 degrees [Celsius] but, with YTM added, they don't come apart until 85 degrees."

The Streptomyces bacteria that produce YTM have also evolved a special enzyme to protect their own DNA from the toxin. Surprisingly, this is a base excision repair enzyme -- called a DNA glycosylase -- that is normally limited to repairing small lesions, not the bulky adducts caused by YTM. Nevertheless, studies have shown that it is extremely effective.

It so happens that one of Streptomyces' competitors, Bacillus cereus, has managed to co-opt the gene that produces this particular enzyme. In Bacillus, however, the enzyme it produces -- called AlkD -- provides only limited protection.

In 2015, Eichman and Mullins reported that, unlike other BER enzymes, AlkD can detect and excise YTM lesions. At the time, they had no idea why it wasn't as effective as its Streptomyces counterpart. Now they do. It turns out that AlkD tightly binds the product that it forms from a YTM lesion, inhibiting the downstream steps in the BER process that are necessary to fully return the DNA to its original, undamaged state. This drastically reduces the effectiveness of the repair process as a whole.

In recent years, biologists have discovered that animals and plants host thousands of different species of commensal bacteria and this microscopic community, called the microbiome, plays a surprisingly important role in their health and well-being. Normally, these bacteria are beneficial -- for example, converting indigestible foods into digestible forms--but they can also cause problems, such as the stomach bacteria Heliobacter pylori that can cause inflammation that produces ulcers.

"We know that bacteria produce compounds like YTM when they are under stress," Eichman observed. "The negative effects this has on their hosts is an unfortunate side effect. So it is very important that we learn as much as we can about how these bacterial toxins work and how bacteria defend against them."
-end-
Graduate research assistant Rongxin Shi also participated in the research, which was funded by National Science Foundation grant MCB-1517695, National Institutes of Health grant R01 ES019625 and Department of Energy's Office of Science grant DE-AC02-06CH11357.

Vanderbilt University

Related Bacteria Articles:

How bees live with bacteria
More than 90 percent of all bee species are not organized in colonies, but fight their way through life alone.
The bacteria building your baby
Australian researchers have laid to rest a longstanding controversy: is the womb sterile?
Detecting bacteria in space
A new genomic approach provides a glimpse into the diverse bacterial ecosystem on the International Space Station.
Hopping bacteria
Scientists have long known that key models of bacterial movement in real-world conditions are flawed.
Bacteria uses viral weapon against other bacteria
Bacterial cells use both a virus -- traditionally thought to be an enemy -- and a prehistoric viral protein to kill other bacteria that competes with it for food according to an international team of researchers who believe this has potential implications for future infectious disease treatment.
More Bacteria News and Bacteria Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Erasing The Stigma
Many of us either cope with mental illness or know someone who does. But we still have a hard time talking about it. This hour, TED speakers explore ways to push past — and even erase — the stigma. Guests include musician and comedian Jordan Raskopoulos, neuroscientist and psychiatrist Thomas Insel, psychiatrist Dixon Chibanda, anxiety and depression researcher Olivia Remes, and entrepreneur Sangu Delle.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...