About 10–15% of tumor cells extend telomeres through the alternative lengthening of telomeres (ALT) mechanism, which is a recombination-dependent replication pathway. It is generally believed that ALT cells are related to the chromatin modification of telomeres. However, the mechanism of ALT needs to be further explored. Here we found that TRIM28/KAP1 is preferentially located on the telomeres of ALT cells and interacts with telomeric shelterin/telosome complex. Knocking down TRIM28 in ALT cells delayed cell growth, decreased the level of C-circle which is one kind of extrachromosomal circular telomeric DNA, increased the frequency of ALT-associated promyelocytic leukemia bodies (APBs), led to telomere prolongation and increased the telomere sister chromatid exchange in ALT cells. Mechanistically, TRIM28 protects telomere histone methyltransferase SETDB1 from degradation, thus maintaining the H3K9me3 heterochromatin state of telomere DNA. Our work provides a model that TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation. In general, our results reveal the mechanism of telomere heterochromatin maintenance and its effect on ALT, and TRIM28 may serve as a target for the treatment of ALT tumor cells.

中文翻译：

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TRIM28 通过保护 SETDB1 免于降解来抑制端粒表型的替代延长

大约 10-15% 的肿瘤细胞通过端粒的替代延长 (ALT) 机制延长端粒，这是一种依赖于重组的复制途径。一般认为ALT细胞与端粒的染色质修饰有关。但ALT的作用机制有待进一步探索。在这里，我们发现 TRIM28/KAP1 优先位于 ALT 细胞的端粒上，并与端粒保护蛋白/端粒复合物相互作用。敲低ALT细胞中的TRIM28会延迟细胞生长，降低C环（一种染色体外环状端粒DNA）的水平，增加ALT相关早幼粒细胞白血病小体（APB）的频率，导致端粒延长并增加端粒姐妹ALT 细胞中的染色单体交换。从机制上讲，TRIM28 保护端粒组蛋白甲基转移酶 SETDB1 免于降解，从而维持端粒 DNA 的 H3K9me3 异染色质状态。我们的工作提供了一个模型，即 TRIM28 通过保护 SETDB1 免于降解来抑制端粒表型的替代延长。总的来说，我们的结果揭示了端粒异染色质维持的机制及其对 ALT 的影响，TRIM28 可能作为治疗 ALT 肿瘤细胞的靶点。