Nucleostemin prevents telomere damage by promoting PML-IV recruitment to SUMOylated TRF1.
Nucleostemin prevents telomere damage by promoting PML-IV recruitment to SUMOylated TRF1.
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DOI：
10.1083/jcb.201109038
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发表时间：
2012-05-28
期刊：
影响因子：
--
通讯作者：
Tsai RY
中科院分区：
文献类型：
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作者：
Hsu JK;Lin T;Tsai RY
一种新的端粒保护机制依赖于nucleostemin介导的PML-IV向端粒的募集以及随后在ALT和端粒酶活性细胞中的RAD 51的募集。连续分裂的细胞必须保护端粒和非端粒DNA损伤，以保持其增殖潜力。在这里，我们报告了一种新的端粒保护机制的核干细胞（NS）的调节。NS耗竭增加了端粒活性（TA+）和端粒替代延长（ALT）细胞中端粒损伤灶的数量，并降低了ALT相关PML小体（APB）相关的受损端粒百分比和ALT细胞中APB的数量。在机制上，NS可以促进PML-IV向TA+和ALT细胞中SUMO化的TRF 1的募集。这一事件是由DNA损伤引起的。支持NS和PML-IV在端粒保护中的重要性，我们证明NS或PML-IV的缺失增加了端粒损伤和畸变的频率，减少了端粒长度，并扰乱了TRF 2 ΔBΔ M诱导的RAD 51的端粒募集。相反，过度表达NS或PML-IV保护ALT和TA+细胞免受端粒损伤。这项工作揭示了端粒保护的新机制。
A novel telomere-protection mechanism relies upon nucleostemin-mediated recruitment of PML-IV to telomeres and subsequent recruitment of RAD51 in both ALT and telomerase-active cells. Continuously dividing cells must be protected from telomeric and nontelomeric DNA damage in order to maintain their proliferative potential. Here, we report a novel telomere-protecting mechanism regulated by nucleostemin (NS). NS depletion increased the number of telomere damage foci in both telomerase-active (TA+) and alternative lengthening of telomere (ALT) cells and decreased the percentage of damaged telomeres associated with ALT-associated PML bodies (APB) and the number of APB in ALT cells. Mechanistically, NS could promote the recruitment of PML-IV to SUMOylated TRF1 in TA+ and ALT cells. This event was stimulated by DNA damage. Supporting the importance of NS and PML-IV in telomere protection, we demonstrate that loss of NS or PML-IV increased the frequency of telomere damage and aberration, reduced telomeric length, and perturbed the TRF2ΔBΔM-induced telomeric recruitment of RAD51. Conversely, overexpression of either NS or PML-IV protected ALT and TA+ cells from telomere damage. This work reveals a novel mechanism in telomere protection.