The parasite Trypanosoma brucei, which causes African sleeping sickness, is like a thief donning a disguise. Every time the host's immune cells get close to destroying the parasite, it escapes detection by rearranging its DNA and changing its appearance.
Now, in research to appear in the advance online April 15 issue of Nature, two laboratories at Rockefeller University have joined forces to reveal how the parasite initiates its getaway, by cleaving both strands of its DNA.
The parasite's survival strategy hinges upon its ability to change its surface coat. The genes that encode the current coat, which is comprised entirely of molecules called variant surface glycoproteins (VSG), are located in 15 to 20 regions near the ends of chromosomes. When the host's immune system has just about killed all of the parasites, some surviving parasites rearrange their DNA and switch their coat, initiating another wave of infection. During this cat-and-mouse game, the immune system never gains the upper hand and the victim dies.
In 2007, George A.M. Cross, head of the Laboratory of Molecular Parasitology, and Oliver Dreesen, a former postdoc in the lab, published a model suggesting that the length of telomeres, which cap the ends of chromosomes, regulate the frequency with which the parasite changes its surface coat. When the telomeres become critically short, they predicted, a break occurs in or adjacent to the actively transcribed VSG gene and triggers a switch.
"Based on the observations we made in 2007, we predicted that doubled-stranded DNA breaks were behind the switch, but we were not able to prove it," says Dreesen, who is now at the Institute of Medical Biology in Singapore. But that all changed when Nina Papavasiliou, head of the Laboratory of Lymphocyte Biology, and Catharine Boothroyd, a postdoc in Nina's lab, began collaborating with Dreesen and Cross, who is André and Bella Meyer Professor at Rockefeller.
"Nina and Catharine had the perfect system to address whether this model was correct or not," says Dreesen. "They had developed a greatly improved assay to measure switching frequency, which is incredibly important, but what was key was that they were able to artificially put breaks upstream of the active VSG gene and see whether or not the surface coat changed."
By working with a DNA-cleaving enzyme from yeast, the team found that a DNA break in a specific region upstream of the active VSG gene causes the parasite to increase its coat-switching frequency by 250 times. During this break-induced recombination, a VSG gene from another chromosome is duplicated and then displaces the previously active VSG gene.
"That was an exciting find," says Boothroyd, "because duplicative gene conversion is the way trypanosomes in the wild also switch their surface coats." As Boothroyd points out, it is also how antibody-producing cells called B lymphocytes chop up and rearrange their DNA in order to destroy the virtually limitless number of foreign invaders that can infect us.
In order for duplicative gene conversion to occur, the team found that the double-stranded breaks occur naturally and specifically in a region upstream of the active VSG gene. It had long been speculated that this conserved repetitive region was important for VSG switching to occur but it had never been experimentally tested. "So detecting these breaks was a critical finding," says Cross. "Something that had not been possible prior to the application of these new techniques."
When the team looked at their first set of data, it not only fit exactly into Dreesen and Cross's prediction but it also suggested a common mechanism by which parasites and humans rearrange their DNA. "It was unbelievable," Dreesen says. "One experiment after another and it just worked."
Thania Benios | EurekAlert!
Further reports about: > B lymphocytes chop > DNA > DNA-cleaving enzyme > Molecular Parasitology > Trypanosoma brucei > Trypanosoma brucei's getaway plan > Trypanosomen > VSG > chromosomes > immune cell > immune system > parasite > parasite wasps > synthetic biology > telomeres > variant surface glycoproteins
Repairing damaged hearts with self-healing heart cells
22.08.2017 | National University Health System
Biochemical 'fingerprints' reveal diabetes progression
22.08.2017 | Umea University
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
22.08.2017 | Health and Medicine
22.08.2017 | Materials Sciences
22.08.2017 | Life Sciences