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

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 I?B kinase (IKK), resulting in activation of the transcription factor NF-?B 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.
Mesh Terms:
Animals, Carrier Proteins, Cell Line, Tumor, Mice, NF-kappa B, Protein Inhibitors of Activated STAT, Receptors, Notch, Signal Transduction, Sumoylation, Telomerase, Telomere, Ubiquitin-Protein Ligases, rap1 GTP-Binding Proteins
Sci Signal
Date: Dec. 29, 2020
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