Function and targeting of telomeric G4 structures

• Applicant: Professorin Dr. Katrin Paeschke
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561054139

Telomeres, the protective ends of eukaryotic chromosomes, have attracted much interest in recent years for their implications in genome stability, cancer and ageing. Maintaining optimal, age-appropriate, telomere length and proper telomere protection are crucial for healthy aging and for reducing the risk for cancer. However, the mechanisms regulating telomere length regulation and protection are not fully understood. Telomeres are composed of short tandem DNA repeats, ending with a 3’ single-stranded G-rich overhang, which binds specialized proteins and governs telomere protection and length regulation. We hypothesize that special four stranded structures, G4s, form at the telomeric overhang and play kye roles in regulating its interactions and functions. G4s can be stabilized by binding of proteins or resolved by helicases. The RTEL1 helicase is essential for telomere length regulation and protection; mutations in RTEL1 cause severe telomere shortening and a fatal disease. To study the roles of telomeric G4, we combine our expertise, unique tools and reagents, Prof. Paeschke in G4s and Prof. Tzfati in RTEL1 and telomere biology. These include high-end methods for detection and manipulation of G4s, patient cells with rare RTEL1 mutations, and a novel method for precise telomere analysis by long-read nanopore sequencing. We will meet frequently, and exchange students, reagents and knowledge to advance our joint research. This unique combination of tools and expertise is promising an exciting collaboration, yielding breakthrough results towards understanding and targeting telomere protection and length regulation in health and disease.

• DFG Programme: Research Grants
• International Connection: Israel
• Partner Organisation: The Israel Science Foundation
• Cooperation Partner: Professor Dr. Yehuda Tzfati