What is it about?
To become immortal, cancer cells must find a way to elongate their telomeres: DNA repeat sequences that protect chromosomes from degradation. Most cancer cells elongate their telomeres by expressing an enzyme called telomerase, but in about 10-15% of cancers, cells use alternative telomere lengthening pathways. These tumors are referred to as "ALT" tumors, for "Alternative Lengthening of Telomeres." Various types of mesenchymal tissue cancers have a strong tendency to become ALT (osteosarcomas, rhabdomyosarcomas, glioblastomas, gliomas…). These are often pediatric cancers, for which there are currently few treatment options. Hope for curative treatments has been revived in recent years with the discovery that ALT cancer cells are highly sensitive to agents that cause problems during DNA replication, such as ATR kinase inhibitors, an enzyme that protects cells against replication issues. Currently, none of these molecules are used as standard treatments in patients, but clinical trials are underway. To identify new proteins that are specifically important for ALT cells and thus potentially targetable therapeutically, we analyzed CRISPR screening databases and identified SUB1 as a new genetic vulnerability specific to ALT cancers. We showed that this protein is recruited to the telomeres specifically in ALT cells and that it protects them from replication issues. When SUB1 is removed from ALT cells, these cells experience telomere stability problems and excessively use telomere elongation pathways, leading to their death. When we combine SUB1 inactivation with ATR inhibitors or co-inactivate FANCM, a DNA helicase previously proposed to be important for ALT cancer viability, we kill these cancer cells even more rapidly.
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Why is it important?
Currently, there are few treatment options for ALT cancers (ex: osteosarcomas, rhabdomyosarcomas, gliomas...) with chemotherapy still occupying center stage despite often limited efficacy. ALT cancer cells experience high levels of of DNA damage at telomeres and its enhancement (e.g. via ATR inhibition) is a promising therapeutic strategy. Sensitivity to ATR inhibition varies amongst ALT cell lines/tumors warranting the development of additional ways to modulate telomeric replication stress. We have identified SUB1, a single-stranded DNA-binding protein, as a vulnerability of ALT cells. SUB1 localizes to ALT telomeres and protects them from deleterious replication stress. SUB1 depletion synergizes with ATR inhibition suggesting that co-targeting SUB1 with other regulators of replication stress at telomeres may kill ALT cancer cells more effectively.
Perspectives
Our work has identified a new regulator of telomere stability and allows us to envision treatment combinations with high efficacy against ALT cancer cells while being relatively harmless to normal cells in patients.
Alexandre Maréchal
Universite de Sherbrooke
Read the Original
This page is a summary of: The single-stranded DNA–binding factor SUB1/PC4 alleviates replication stress at telomeres and is a vulnerability of ALT cancer cells, Proceedings of the National Academy of Sciences, January 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2419712122.
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