SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling

Targeting the binding partners of the telomere protein RAP1 could halt the growth of ALT-proficient tumors. Control ALT (to) delete (tumors) With repetitive divisions, a cell’s telomeres (the ends of chromosomes) shorten to a point at which the cell can no longer divide. However, tumor cells are adept at maintaining telomere length. Robinson et al. uncovered a mechanism that supports a type of telomere maintenance called alternative lengthening of telomeres (ALT) (see also the Focus by Churikov and Géli). In osteosarcoma and breast cancer cell lines that maintain telomere length through ALT, the telomere-binding protein RAP1 was SUMOylated, dissociated from telomeres, and localized to the cytoplasm. There, it promoted NF-κB–to–Notch signaling, which mediated ALT-associated gene expression. The findings reveal the signaling mechanisms that coordinate telomere maintenance and potential therapeutic opportunities to halt the growth of some tumors. The maintenance of telomere length supports repetitive cell division and therefore plays a central role in cancer development and progression. Telomeres are extended by either the enzyme telomerase or the alternative lengthening of telomeres (ALT) pathway. Here, we found that the telomere-associated protein SLX4IP dictates telomere proteome composition by recruiting and activating the E3 SUMO ligase PIAS1 to the SLX4 complex. PIAS1 SUMOylated the telomere-binding protein RAP1, which disrupted its interaction with the telomere-binding protein TRF2 and facilitated its nucleocytoplasmic shuttling. In the cytosol, RAP1 bound to IκB kinase (IKK), resulting in activation of the transcription factor NF-κB and its induction of Jagged-1 expression, which promoted Notch signaling and the institution of ALT. This axis could be targeted therapeutically in ALT-driven cancers and in tumor cells that develop resistance to antitelomerase therapies. Our results illuminate the mechanisms underlying SLX4IP-dependent telomere plasticity and demonstrate the role of telomere proteins in directly coordinating intracellular signaling and telomere maintenance dynamics.

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