Potts Patrick Ryan, Yu Hongtao
Department of Pharmacology, The University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390-9041, USA.
Nat Struct Mol Biol. 2007 Jul;14(7):581-90. doi: 10.1038/nsmb1259. Epub 2007 Jun 24.
Most cancer cells activate telomerase to elongate telomeres and achieve unlimited replicative potential. Some cancer cells cannot activate telomerase and use telomere homologous recombination (HR) to elongate telomeres, a mechanism termed alternative lengthening of telomeres (ALT). A hallmark of ALT cells is the recruitment of telomeres to PML bodies (termed APBs). Here, we show that the SMC5/6 complex localizes to APBs in ALT cells and is required for targeting telomeres to APBs. The MMS21 SUMO ligase of the SMC5/6 complex SUMOylates multiple telomere-binding proteins, including TRF1 and TRF2. Inhibition of TRF1 or TRF2 SUMOylation prevents APB formation. Depletion of SMC5/6 subunits by RNA interference inhibits telomere HR, causing telomere shortening and senescence in ALT cells. Thus, the SMC5/6 complex facilitates telomere HR and elongation in ALT cells by promoting APB formation through SUMOylation of telomere-binding proteins.
大多数癌细胞激活端粒酶以延长端粒并获得无限增殖潜能。一些癌细胞无法激活端粒酶，而是利用端粒同源重组（HR）来延长端粒，这一机制被称为端粒替代延长（ALT）。ALT细胞的一个标志是端粒被募集到PML小体（称为APB）。在这里，我们表明SMC5/6复合物定位于ALT细胞中的APB，并且是将端粒靶向APB所必需的。SMC5/6复合物的MMS21 SUMO连接酶对多种端粒结合蛋白进行SUMO化修饰，包括TRF1和TRF2。抑制TRF1或TRF2的SUMO化会阻止APB的形成。通过RNA干扰耗尽SMC5/6亚基会抑制端粒HR，导致ALT细胞中的端粒缩短和衰老。因此，SMC5/6复合物通过对端粒结合蛋白进行SUMO化修饰促进APB形成，从而促进ALT细胞中的端粒HR和延长。
