Tianyi Gao1, Jun Xuan Ang1, Jiayi Shen1, Thomasin Brind1, Thi Minh Ngoc Trinh1, Joshua Mills1, Lisa J Alcock2 and Yu Heng Lau1
1 School of Chemistry, The University of Sydney, Camperdown, NSW, Australia.
2 School of Molecular and Life Sciences, Curtin University, Bentley, WA, Australia.
Telomeric repeat binding factor 2 (TRF2) is a core component of the Shelterin complex that binds directly to double-stranded telomeric DNA.1 This interaction prevents its misrecognition as a DNA double-stranded break, thus protecting it from nucleolytic degradation. In some cancers, the protective role of TRF2 is co-opted to suppress genomic instability that arises due to cancerous mutations, thus attracting interest as a potential therapeutic target.2, 3
In this work, we target the TRFH domain of TRF2, a region that is both responsible for driving homodimerisation as well as recruitment of accessory proteins that help resolve replication stress at telomeres. As the recruitment site represents a protein-protein interface, peptides are particularly suitable inhibitors.
We demonstrate the use of phage display as a viable strategy for identifying novel cyclic and linear peptides that bind the TRFH domain of TRF2. These peptides serve as useful tools that provide a foundation for the development of more drug-like inhibitors of TRF2 in cancer.
References
1. Schmutz, I.; de Lange, T., Shelterin. Curr. Biol. 2016, 26 (10), 397-399.
2. Fairall, L.; Chapman, L.; Moss, H.; Lange, T. d.; Rhodes, D., Structure of the TRFH Dimerization Domain of the Human Telomeric Proteins TRF1 and TRF2. Mol. Cell 2001, 8 (2), 351-361.
3. Janovic, T.; Perez, G. I.; Boelting, G.; Schmidt, J. C., TRF1 and TRF2 Form Distinct Shelterin Subcomplexes at Telomeres. Cell Rep. 2025, 44 (9), 1-24.