Poster Presentation The 46th Lorne Conference on Protein Structure and Function 2021

Development of stapled peptides inhibiting the interaction between FANCM and RMI complex as a possible therapeutic strategy for ALT cancers (#301)

Tianyi Gao 1 , Quynh Vu 1 , Haritha Krishna Sudhakar 1 , Yu Heng Lau 1
  1. The University of Sydney, Camperdown, NSW, Australia

Telomeres are repetitive sequences located at the end of chromosomes to prevent loss of genetic information due to the semi-conservative nature of DNA replication. As a result, telomeres get shortened after each cell division, until a critical length triggers the DNA damage response (DDR), leading to cellular senescence or apoptosis.1 About 5-15% of the cancer cells utilise alternative lengthening of telomeres (ALT) to maintain telomere length and acquire immortality1,2. ALT-positive cancers are more resistant to existing anti-cancer therapeutics, contributing to a higher risk of patient death.

ALT activity is delicately regulated by two protein complexes – FANCM and the Bloom’s complex, which associate via a strong hydrophobic interaction between the MM2 domain of FANCM and the RMI subcomplex of the Bloom’s Complex, where the residues of MM2 project into the binding pockets on RMI complex in a “knobs-into-holes” fashion3.  Removal of MM2 from FANCM completely abrogated the interaction with RMI, which is lethal to ALT-positive cells, posing as a possible treatment for ALT cancers4. The aim of this project is to develop an MM2 mimic with greater binding affinity to inhibit the interaction between RMI and FANCM. In this work, I will discuss our progress toward synthesising the MM2 analogues, peptide stapling using different types of linkers, as well as strategies to resolve some problems arose.

  1. (1) Okamoto, K.; Seimiya, H. Revisiting Telomere Shortening in Cancer. Cells 2019, 8 (2), 107. https://doi.org/10.3390/cells8020107.
  2. (2) O’Rourke, J. J.; Bythell-Douglas, R.; Dunn, E. A.; Deans, A. J. ALT Control, Delete: FANCM as an Anti-Cancer Target in Alternative Lengthening of Telomeres. Nucleus 2019, 10 (1), 221–230. https://doi.org/10.1080/19491034.2019.1685246.
  3. (3) Hoadley, K. A.; Xue, Y.; Ling, C.; Takata, M.; Wang, W.; Keck, J. L. Defining the Molecular Interface That Connects the Fanconi Anemia Protein FANCM to the Bloom Syndrome Dissolvasome. Proc. Natl. Acad. Sci. U. S. A. 2012, 109 (12), 4437–4442. https://doi.org/10.1073/pnas.1117279109.
  4. (4) Lu, R.; O’Rourke, J. J.; Sobinoff, A. P.; Allen, J. A. M.; Nelson, C. B.; Tomlinson, C. G.; Lee, M.; Reddel, R. R.; Deans, A. J.; Pickett, H. A. The FANCM-BLM-TOP3A-RMI Complex Suppresses Alternative Lengthening of Telomeres (ALT). Nat. Commun. 2019, 10 (1). https://doi.org/10.1038/s41467-019-10180-6.