Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Sci Signal. 2021 Jun 29;14(689):eabe9613. doi: 10.1126/scisignal.abe9613.
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.
端粒长度的维持支持细胞的重复分裂，因此在癌症的发生和发展中起着核心作用。端粒通过端粒酶或端粒的替代性延长（ALT）途径来延长。在这里，我们发现端粒相关蛋白 SLX4IP 通过招募并激活 E3 SUMO 连接酶 PIAS1 到 SLX4 复合物，从而决定端粒蛋白质组的组成。PIAS1 对端粒结合蛋白 RAP1 进行 SUMO 化修饰，破坏了 RAP1 与端粒结合蛋白 TRF2 的相互作用，并促进了其核质穿梭。在细胞质中，RAP1 与 IκB 激酶（IKK）结合，导致转录因子 NF-κB 的激活及其诱导的表达，从而促进了 Notch 信号转导和 ALT 的建立。在 ALT 驱动的癌症和对抗端粒酶治疗产生耐药性的肿瘤细胞中，可以对该轴进行治疗性靶向。我们的研究结果阐明了 SLX4IP 依赖性端粒可塑性的机制，并证明了端粒蛋白在直接协调细胞内信号和端粒维持动力学方面的作用。
