TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation.
TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation.
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TRIM28 通过保护 SETDB1 免遭降解来抑制端粒表型的选择性延长
DOI：
10.1186/s13578-021-00660-y
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发表时间：
2021-07-30
影响因子：
7.5
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Wang C;Songyang Z;Huang Y
大约 10-15% 的肿瘤细胞通过替代性端粒延长 (ALT) 机制延长端粒，这是一种重组依赖性复制途径。一般认为ALT细胞与端粒染色质修饰有关。但 ALT 的作用机制尚需进一步探讨。在这里，我们发现 TRIM28/KAP1 优先位于 ALT 细胞的端粒上，并与端粒庇护蛋白/端体复合物相互作用。敲除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ALT细胞中的端粒姐妹染色单体交换。从机制上讲，TRIM28 保护端粒组蛋白甲基转移酶 SETDB1 免遭降解，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，TRIM28 通过保护 SETDB1 免于降解来抑制端粒表型的选择性延长。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 ALT 肿瘤细胞的治疗靶点。在线版本包含可在 10.1186/s13578-021-00660-y 获取的补充材料。
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. The online version contains supplementary material available at 10.1186/s13578-021-00660-y.
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影响因子：
16.8
作者：
Iwase, Shigeki;Xiang, Bin;Ghosh, Sharmistha;Ren, Ting;Lewis, Peter W.;Cochrane, Jesse C.;Allis, C. David;Picketts, David J.;Patel, Dinshaw J.;Li, Haitao;Shi, Yang
通讯作者：
Shi, Yang
影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
DOI：
10.1038/nrg3246
发表时间：
2012-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1016/0921-8734(91)90018-7
发表时间：
1991-03-01
期刊：
MUTATION RESEARCH
影响因子：
--
作者：
HARLEY, CB
通讯作者：
HARLEY, CB
影响因子：
10.5
作者：
Friedman, JR;Fredericks, WJ;Rauscher, FJ
通讯作者：
Rauscher, FJ