Identification of endogenous TERRA-ribonucleoprotein components and characterization of their function in telomere biology

• Applicant: Dr. Sascha Feuerhahn
• Subject Area: General Genetics and Functional Genome Biology
• Term: from 2011 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 193298504

Telomeres form the ends of eukaryotic chromosomes. A set of telomere-specific components plays fundamental roles as guardians of genome integrity and suppressors of tumorigenesis. Recently, a novel and unexpected telomere component has been described: the telomeric repeat containing RNA (TERRA). Several observations point towards an essential role of TERRA in the maintenance of telomere integrity. Nevertheless, precise knowledge about the regulation of this long non-coding RNA is still sparse. To address this issue, this proposal aims at the characterization of TERRA-binding proteins with regard to their function in TERRA and telomere metabolism. Hereby, endogenous TERRA and its associated factors, also called TERRA-ribonucleoprotein complexes (TERRA-RNPs), will be isolated from a human cell line. Next, TERRA-binding proteins will be identified by mass spectrometry. By genetic manipulation of the identified factors, their role in TERRA-metabolism as well as telomere maintenance will be assessed. This will elucidate how TERRA impinges on chromosome stability and will further identify new factors implicated in telomere integrity and the suppression of carcinogenesis. Not only may this uncover a novel mechanism of how a non-coding RNA can control telomere/genome integrity, but also serve as a paradigm for the mode of action and regulation of other non-coding transcripts. Furthermore, the characterization of factors that modulate TERRA and in turn control telomere maintenance may identify novel and promising targets for cancer therapy. Finally, characterizing TERRA-RNPs will expand our knowledge on the molecular mechanisms causative for human diseases associated with telomere dysfunction.

• DFG Programme: Research Fellowships
• International Connection: Switzerland
• Host: Professor Dr. Joachim Lingner