TSPYL5 depletion induces specific death of ALT cells through USP7-dependent proteasomal degradation of POT1
(2019) Molecular Cell — Vol. 75, n° 3, p. 469-482 (2019)
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- A significant fraction (~10%) of cancer cells maintain their telomere length via a telomerase-independent mechanism known as Alternative Lengthening of Telomeres(ALT). Currently, there are no known molecular, ALT-specific, therapeutic target. We have identified TSPYL5 (Testis Specific Y-encoded-Like Protein 5) as a PML body component, co-localizing with ALT telomeres and critical for ALT+ cell viability. TSPYL5 was described as an inhibitor of the USP7 deubiquitinase. We report that TSPYL5 prevents the poly-ubiquitination of POT1 – a shelterin component – and protects POT1 from proteasomal degradation, exclusively in ALT+ cells. USP7 depletion rescued POT1 poly-ubiquitination and loss, suggesting that the deubiquitinase activates POT1 E3 ubiquitin ligase(s). Similarly, PML depletion suppressed POT1 poly-ubiquitination, suggesting an interplay between USP7 and PML to trigger POT1 degradation in TSPYL5-depleted ALT+ cells. We demonstrate that ALT telomeres need to be protected from POT1 degradation in ALT-associated PML bodies, and identify TSPYL5 as a ALT+ cancer-specific therapeutic target.
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Episkopou, C., Diman, A., Claude, E. L., Viceconte, N., & Decottignies, A. (2019). TSPYL5 depletion induces specific death of ALT cells through USP7-dependent proteasomal degradation of POT1. Molecular Cell, 75(3), 469-482. https://hdl.handle.net/2078.5/98507 (Original work published 2019)