SLX4IP Promotes RAP1 SUMOylation by PIAS1 to Coordinate Telomere Maintenance Through NF-κB and Notch Signaling

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2021 Jun 30

PMID 34187905

Citations 12

Authors

Nathaniel J Robinson

Masaru Miyagi

Jessica A Scarborough

Jacob G Scott

Derek J Taylor

William P Schiemann

Affiliations

Soon will be listed here.

Abstract

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 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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