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
North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich
Researchers Discover New Anti-Cancer Protein
22.03.2018 | Universität Basel
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.
In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...
19.03.2018 | Event News
16.03.2018 | Event News
13.03.2018 | Event News
22.03.2018 | Trade Fair News
22.03.2018 | Earth Sciences
22.03.2018 | Earth Sciences