SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-{kappa}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 IB 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.

Source: Signal Transduction Knowledge Environment - June 29, 2021 Category: Science Authors: Robinson, N. J., Miyagi, M., Scarborough, J. A., Scott, J. G., Taylor, D. J., Schiemann, W. P. Tags: STKE Research Articles Source Type: news