Alternative routes to immortality
Every time a cell divides, the ends of chromosomes – the threads of DNA residing in the nucleus – shorten a bit. Once the chromosome ends, called telomeres, become too short, cells normally stop dividing. Scientists from the German Cancer Research Center (DKFZ) have now discovered how cancer cells make use of specific DNA repair enzymes to extend the telomeres. In this way, they escape the natural stop signal and can divide without limits. The Federal Ministry of Education and Research (BMBF) supports the project as part of the e:Med research initiative.
Our genetic material is packaged into proteins as chromosomes in the cell’s nucleus. The ends of all chromosomes, called telomeres, consist of multiple repeats of specific DNA sequences that shorten every time a cell divides. As the cell ages, the telomeres become very short and the cell stops dividing. Telomeres act like an hourglass that runs out in order to prevent cells from dividing more than 50 to 60 times.
For cancer cells, it is therefore crucial to be able to reset the hourglass. Most tumors do so by simply reactivating the gene for telomerase, an enzyme that normally extends telomeres only in embryonic stem cells.
However, about ten percent of all cancer types, such as childhood brain cancer, use an alternative mechanism to extend their telomeres. Scientists led by Dr. Karsten Rippe at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and Heidelberg University have now taken a closer look at this complex process.
The researchers already knew that in the alternative process of telomere lengthening, tiny protein aggregates called nucleoli assemble at the telomeres. In order to identify the nucleoli components that are involved in the process, Rippe’s team individually turned off approximately 100 candidate proteins in the cancer cells.
Using automated microscopy images, the investigators analyzed over 20 million images that showed the effects of losing the individual proteins. They identified 29 proteins that play a role in the complex process of alternative telomere lengthening. The actual extension of the chromosome ends happens because the nucleoli that are attached to the telomere activate specific DNA repair proteins that add the missing sequences.
“We now know the molecular players that are involved in alternative telomere lengthening. Thus, we know new targets to block this process in tumors that use this alternative mechanism,” says Katharina Deeg, one of the first authors of the publication. Collaborating with colleagues from the University Hospitals of Hamburg and Heidelberg, the researchers are currently studying glioblastoma and prostate cancer cells from patients to find out how individual tumor types differ in telomere extension and how this impacts the course of the disease.
The Federal Ministry of Education and Research (BMBF) has supported the project as part of the e:Med research initiative.
Osterwald, S., Deeg, K. I., Chung, I., Parisotto, D., Wörz, S., Rohr, K., Erfle, H. & Rippe, K.: PML induces compaction, partial TRF2 depletion and DNA damage signaling at telomeres and promotes alternative lengthening of telomeres. J. Cell Sci. 2015, DOI 10.1242/jcs.148296.
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.