SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling.
SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling.
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DOI：
10.1126/scisignal.abe9613
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发表时间：
2021-06-29
影响因子：
7.3
通讯作者：
Schiemann WP
中科院分区：
文献类型：
--
作者：
Robinson NJ;Miyagi M;Scarborough JA;Scott JG;Taylor DJ;Schiemann WP
端粒长度的维持支持重复的细胞分裂，因此在癌症的发展和进展中起着核心作用。端粒通过端粒酶或端粒替代延长（ALT）途径延长。在这里，我们发现，端粒相关蛋白SLX 4 IP决定端粒蛋白质组组成的招募和激活E3 SUMO连接酶PIAS 1的SLX 4复合物。PIAS 1 SUMO化端粒结合蛋白RAP 1，破坏其与端粒结合蛋白TRF 2的相互作用，促进其核质穿梭。在胞浆中，RAP 1与IκB激酶（IKK）结合，激活转录因子NF-κB，诱导Jagged-1表达，促进Notch信号传导，形成ALT。该轴可以在ALT驱动的癌症和对抗端粒酶疗法产生抗性的肿瘤细胞中进行治疗靶向。我们的研究结果阐明了SLX 4 IP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传导和端粒维持动力学中的作用。
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 anti-telomerase 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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DOI：
10.1126/science.1170633
发表时间：
2009-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
de Lange T
通讯作者：
de Lange T
影响因子：
16
作者：
Comb, William C.;Hutti, Jessica E.;Baldwin, Albert S.
通讯作者：
Baldwin, Albert S.
影响因子：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
5.3
作者：
Caslini, Corrado;Connelly, James A.;Hess, Jay L.
通讯作者：
Hess, Jay L.
影响因子：
64.8
作者：
Cho, Uhn Soo;Xu, Wenqing
通讯作者：
Xu, Wenqing