Nucleostemin inhibits TRF1 dimerization and shortens its dynamic association with the telomere
Nucleostemin inhibits TRF1 dimerization and shortens its dynamic association with the telomere
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DOI：
10.1242/jcs.089672
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发表时间：
2011-11-01
影响因子：
4
通讯作者：
Tsai, Robert Y. L.
中科院分区：
文献类型：
--
作者：
Meng, Lingjun;Hsu, Joseph K.;Tsai, Robert Y. L.
TRF1是端粒加帽复合物的关键组分，并以同源二聚体的形式结合双链端粒DNA。到目前为止，还不清楚TRF1二聚化是否与其端粒结合一致，或者在其结合端粒之前受到主动控制，以及在后一种情况下，该事件如何影响其端粒缔合。我们以前发现，TRF 1的二聚化和端粒结合可以增加GNL3L，这是脊椎动物的核干细胞蛋白（NS）的paraffin。在这里，我们表明，NS和GNL3L直接结合TRF1，但竞争性地通过TRF1的两个独立的结构域。与GNL3L相反，NS通过其取代TRF1结合的GNL3L的能力不确定的机制阻止TRF1二聚化。此外，NS能够缩短正常和TRF 2（Δ B Δ M）诱导的端粒损伤细胞中TRF 1与端粒的动态关联，而不影响体内端粒结合的TRF 1蛋白的量。重要的是，NS显示出对端粒功能障碍诱导的病灶形成的保护功能。这项工作表明，TRF1二聚化是积极和相反的NS和GNL3L染色体外调节。改变核质中TRF1单体与二聚体的相对数量可能会影响TRF1与端粒的动态关联以及受损端粒的修复。
TRF1 is a key component of the telomere-capping complex and binds double-strand telomeric DNA as homodimers. So far, it is not clear whether TRF1 dimerization coincides with its telomere binding or is actively controlled before it binds the telomere, and in the latter case, how this event might affect its telomere association. We previously found that TRF1 dimerization and its telomere binding can be increased by GNL3L, which is the vertebrate paralogue of nucleostemin (NS). Here, we show that NS and GNL3L bind TRF1 directly but competitively through two separate domains of TRF1. In contrast to GNL3L, NS prevents TRF1 dimerization through a mechanism not determined by its ability to displace TRF1-bound GNL3L. Furthermore, NS is capable of shortening the dynamic association of TRF1 with the telomere in normal and TRF2(Delta B Delta M)-induced telomere-damaged cells without affecting the amount of telomere-bound TRF1 proteins in vivo. Importantly, NS displays a protective function against the formation of telomere-dysfunction-induced foci. This work demonstrates that TRF1 dimerization is actively and oppositely regulated by NS and GNL3L extrachromosomally. Changing the relative amount of TRF1 monomers versus dimers in the nucleoplasm might affect the dynamic association of TRF1 with the telomere and the repair of damaged telomeres.