Stevers Nicholas O, Kim Somang, Yuan Jimmy Bo, Barger Carter J, Hong Chibo, Lenzo Olivia, McKinney Andrew M, Wu Samuel H, Lee Yu Jin, Kwok Darwin W, Suwala Abigail K, Appin Christina L, Gordan John D, Molinaro Annette M, Song Jun S, Costello Joseph F
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
Department of Physics, University of Illinois, Urbana-Champaign, Champaign, IL, USA; Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Champaign, IL, USA; Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Champaign, IL, USA.
Mol Cell. 2025 Jun 19;85(12):2337-2354.e9. doi: 10.1016/j.molcel.2025.05.026. Epub 2025 Jun 12.
Activating mutations in the telomerase reverse transcriptase (TERT) promoter are prevalent in cancer and enable limitless cell division characteristic of immortal cells. Solving the immortality mechanism represents a major step toward selective reversal in cancer cells. TERT promoter (TERTp) mutations create a de novo E26 transformation-specific (ETS) transcription factor binding motif. Here, we analyzed 53 cell lines representing 16 cancer types and 6 recurrent TERTp mutations and found that the GA-binding protein (GABP) tetramer is responsible for promoter activation in all cases. Surprisingly, TERT expression is maintained after tetramer depletion. Further investigation revealed an underlying network of auto-suppression among the GABP subunits. Release from it drives TERT maintenance via upregulated GABP dimers or a paralogous tetramer. The GABPB1L tetramer is therefore a pan-cancer, pan-mutation activator of the mutant TERT promoter, but it is replaceable. Domains shared by the three GABP complexes, rather than solely the B1L tetramer, are mutation-specific vulnerabilities.
端粒酶逆转录酶（TERT）启动子中的激活突变在癌症中普遍存在，并能实现永生化细胞特有的无限细胞分裂。解决永生机制是癌细胞选择性逆转的重要一步。TERT启动子（TERTp）突变产生了一个全新的E26转化特异性（ETS）转录因子结合基序。在此，我们分析了代表16种癌症类型的53个细胞系和6种常见的TERTp突变，发现GA结合蛋白（GABP）四聚体在所有情况下都负责启动子激活。令人惊讶的是，四聚体耗尽后TERT表达仍得以维持。进一步研究揭示了GABP亚基之间存在自动抑制的潜在网络。从该网络中释放出来可通过上调的GABP二聚体或同源四聚体驱动TERT维持。因此，GABPB1L四聚体是突变型TERT启动子的一种泛癌、泛突变激活剂，但它是可替代的。三种GABP复合物共有的结构域，而非仅B1L四聚体，是突变特异性的脆弱点。
