RNA-vermittelte DNA Reparatur als prinzipieller Auslöser rekurrenter Krebserkrankungen

• Applicant: Professor Dr. Rolf Marschalek
• Subject Area: Hematology, Oncology
• Term: from 2017 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 353065907

Tumors usually arise because somatic cells aquire a certain number of somatic mutations over time, or aquire spontaneously a specific chromosomal translocation (CT). The database of the Sanger Cancer Institute has identified so far 595 cancer genes, of which 360 are recurrently found in CTs. CTs usually occur in important genes which subsequently lead to the expression of strong oncogenic fusion proteins driving the different cancers. But how can we explain that different patients carry the same chromosomal translocations, like e.g. a BCR-ABL translocation? A rational explanation for this phenomenon is offered by "non-genomically encoded fusion transcripts" (NGEFT) that can be found in normal human cells that do not exhibit any genetic aberration. We postulate that these NGEFTs may cause CTs when they encounter dsDNA breaks. These genetic lesions can be induced by exogenously applied chemicals, or by endogenous processes like apoptosis or gene transcription. Therefore, we want to demonstrate experimentally that specific NGEFT's are able to induce chromosomal translocations, and moreover, demonstrate that "genomic RNA" is per se being used in human cells for the repair of genetic lesions in order to maintain genetic integrity. The mechanism of this novel biological process will be investigated as well.

• DFG Programme: Reinhart Koselleck Projects