Gadd45a Wakes Sleeping Genes
Scientists at the DKFZ discover an enzym that activates epigenetically silenced genes
For several years now, cancer researchers have been studying a mechanism that contributes to the development of malignant tumors: The cell attaches small molecules containing a carbon atom, called methyl groups, to specific building blocks of DNA, thereby individually switching off the genes thus labeled. This silencing also affects the function of many tumor suppressor genes, which, in their unmethylated state, put the brakes on uncontrolled cell growth. In contrast to `real´ mutations, where DNA building blocks are exchanged or lost, these epigenetic changes are reversible. Therefore, this mechanism is considered to be a promising approach in fighting cancer.
The cell uses this mechanism of putting genes to sleep and waking them up again when needed for many regulation processes. Scientists have already found out how the methyl groups are attached. The reverse process of demethylation, however, has been poorly understood so far. Researchers from the divisions of Professor Dr. Christof Niehrs and Professor Dr. Frank Lyko at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now been able to identify a protein called Gadd45a as a key player in demethylation. Gadd45a is a long known protein that is involved in many cellular processes.
The researchers showed in a series of experiments that an increase of Gadd45a levels in the cells wakes deactivated genes from their sleep. Control experiments showed that methyl groups are indeed no longer attached to genes thus reactivated. In contrast, if Gadd45a is deliberately switched off, hypermethylation of many DNA areas is the result. When removing the methyl groups, as the investigators have further demonstrated, Gadd45a interacts with enzymes that are involved in DNA repair. The data obtained by Niehrs and Lyko indicate that Gadd45a induces DNA-cutting enzymes of the DNA repair troops to remove the methylated areas, which are subsequently replaced again by unmethylated building blocks.
"The role of Gadd45a for cancer development is shown in mice lacking this protein," Niehrs und Lyko explained. "These animals suffer particularly often from malignant tumors. Now we are able to make sense of this: The knockdown of Gadd45a in these animals causes excessive methylation of tumor suppressor genes so that many of the natural tumor `brakes´ fail to work. Therefore, Gadd45a may also become an interesting target for clinical oncology."
Gadd45a promotes epigenetic gene activation by repair mediated DNA demethylation. Guillerma Barreto, Andrea Schäfer, Joachim Marhold, Dirk Stach, Suresh K. Swaminathan, Vikas Handa, Gabi Döderlein, Nicole Maltry, Wei Fu, Frank Lyko and Christof Niehrs, Nature 2007, DOI: 10.1038/nature05515
With more than 3,000 employees, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is Germany’s largest biomedical research institute. DKFZ scientists identify cancer risk factors, investigate how cancer progresses and develop new cancer prevention strategies. They are also developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to questions relating to cancer.
To transfer promising approaches from cancer research to the clinic and thus improve the prognosis of cancer patients, the DKFZ cooperates with excellent research institutions and university hospitals throughout Germany:
The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.
