Dresden scientists develop a sensor for the most important human cancer gene
Molecular “detector” recognizes most frequent cancer-mutation in cells and initiates to kill them
If it burns in a house smoke detectors alert us hence protecting life. A molecular smoke alert has now been developed by Dresden researchers for the TP53 gene, the most important human cancer gene. The alert goes on if the TP53 gene is mutated in cells. The molecular smoke detector works like a TP53 sensor, which monitors the correct function of the gene. A non-functional TP53 gene is going to activate the sensor, which initiates cell death. Results from this study from the research team of Prof. Frank Buchholz are now published in the journal „Nature Communications“.
Cancer is caused by changes in the human genome. Mutations in oncogenes and in tumor suppressor genes accumulate unrecognized over time and lead to uncontrolled cell proliferation eventually. In 50% of all human tumors the tumor suppressor gene TP53 is no longer functional being the most frequently mutated cancer gene. Scientists from the Universitäts KebsCentrum UCC at the Universitätsklinikum Carl Gustav Carus, the Nationalen Centrum für Tumorerkrankungen NCT Dresden and the Deutsches Konsortium für Translationale Krebsforschung DKTK Dresden concluded that the formation of a TP53 sensor could suppress tumor formation at a very early stage.
To achieve this they designed a genetic element that makes cell function dependent on normal TP53. If the TP53 function is interrupted, the sensor gets activated and initiates cell death. ”We treat cancer cells long after they have gone through the transformation process,” says Prof. Dr. med. Frank Buchholz describing the current situation. As a result, therapy is often too late to be able to eliminate all cancer cells in the body. Furthermore, due to additional mutations, therapy-resistant clones quickly emerge from some cancer cells.
“The TP53 sensor enables an active precocious intervention for the first time. Our results show that cells with TP53 mutations can be selectively detected and eliminated at an early stage. Hence, the transformation process is prevented.” The researchers plan to use their initial findings to develop new cancer diagnostics and to establish a protection system against cancer mutations in the long-term.
ERC ADVANCED GRANT
Frank Buchholz, Professor for Medical Systems Biology at the TU Dresden Faculty of Medicine Carl Gustav Carus was awarded an ERC Advanced Grant worth EUR 2.4 million for his research in the field of targeted genome surgery based on evolved site-specific recombinases. The team headed by Prof. Buchholz already succeeded in developing a designer recombinase (Brec1) that is capable of specifically removing the provirus from infected cells of most primary HIV-1 isolates found in humans. Now Frank Buchholz’ research is also focusing on various other diseases. “The generation of molecular scalpels, such as the Brec1 recombinase, will change medical practice. Not only HIV patients will likely benefit from this development, but presumably also many other patients. We are about to witness the beginning of the genome surgery era”, predicts the head of the Dresden research group, Prof. Frank Buchholz. In the funded “GenSurge” project, a “genome-editing platform” will be developed which allows efficient and safe DNA modifications without triggering cell intrinsic DNA repair.
PROVIREX IS WINNER OF THE INNOVATIONSPREIS DER BIOREGIONEN 2017
With 37 Million HIV-positive people and more than 2 Million new infections annually, HIV remains a major world health challenge. Even though enormous advances have been made in HIV treatment, a complete cure from the disease is still not possible. Indeed, the propagation of the virus in the body can nowadays be held in check through medication, but the provirus remains present in cells of the body.
A team of researchers from the Department of Medical Systems Biology at the TUD as well as the research unit Antiviral Strategies at the HPI in Hamburg employed directed molecular evolution to generate a designer recombinase (Brec1), which can precisely remove the provirus from the majority (>90%) of clinical HIV-1 isolates found in humans.
The team now demonstrated for the first time, that the approach works on cells directly isolated from HIV-1 patients. Importantly, the antiviral effects were accomplished without measurable cytotoxic or genotoxic side effects. Based on these findings, Brec1 represents a promising candidate for possible applications in improved HIV therapies.