Analysis of Alternative Lengthening of Telomeres Mediated by LLPS in Cancers

Telomeres are DNA-protein complexes that protect eukaryotic chromosome ends from being incorrectly repaired by the DNA damage repair system. Telomeres shorten during each cell division, ultimately leading to cellular senescence and apoptosis. During tumorigenesis, tumor cells almost universally counteract telomere shortening by activating the telomere maintenance mechanism (TMM) of telomere lengthening to ensure cell proliferation potential and genomic stability. Alternative lengthening of telomeres (ALT) is the most frequently activated TMM in tumors of mesenchymal and neuroepithelial origin. The ALT pathway involves the assignment of telomere lengthening components to membrane-free promyelocytic leukemia (PML) nucleosomes.

Fig. 1. LLPS is a strategy for the alternative lengthening of telomeres. (Tong X, et al., 2022)

Customized Services

Oncogenic transformations can be immortalized using TMM. Studies have shown that liquid-liquid phase separation (LLPS) is extensively involved in TMM and counteracts the deleterious effects of telomere shortening induced by cell cycle acceleration in cancer cells. Our experts are committed to developing LLPS as a strategy for alternative lengthening of telomeres, and exploring possible cancer therapeutic targets in the ALT pathway.

CD BioSciences offers specialized services to analyze LLPS-mediated alternative lengthening of telomeres in cancers, such as melanoma, B-cell lymphoma and chronic lymphocytic leukemia. Our laboratory has proven ex vivo and in vitro LLPS induction platforms to characterize the ALT pathway to form ALT-associated PML bodies (APB) and to analyze the multivalent interactions between SUMO and SUMO-interaction motif (SIM)-containing proteins in APB.

APB behaves as a liquid condensate that aggregates telomeres via Sumo-Sim-dependent LLPS to drive telomere lengthening. This is the reason why some cancer cells readily counteract telomere shortening to prolong cell cycle progression. Our technical team is focused on developing ALT-associated tumor-targeting drugs. In combination with studies on the mechanisms of the ALT pathway, we have developed the following potential therapeutic targets for ALT:

• Development of ATR inhibitors and G-quadruplex stabilizers to inhibit homologous recombination and further suppress ALT cell activity.
• Induction of ALT cell death by altering the homeostasis of ALT telomeres.
• Inhibition of the proliferation of ALT-associated tumor cells by inducing telomere fusion in ALT cells.
• Selective killing of ALT-associated tumors by inhibiting the activity of PARP or proteins involved in the inhibition of ALT telomere fusion.

Combining proteomics, transcriptomics, imaging, genetics, epidemiology and computer data, CD BioSciences aims to analyze the molecular basis of the LLPS-mediated ALT pathway in cancers, to help our clients develop therapeutic strategies for ALT tumors. If you are interested in our services, please feel free to contact us.