The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity.
The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity.
复制标题
端粒蛋白TPP1的TEL斑块介导端粒酶募集和加工性。
作者：
人类染色体末端被shelterin覆盖，shelterin是一种蛋白质复合物，可以保护天然末端不被识别为DNA损伤位点，并调节端粒复制酶端粒酶。Shelterin包括异二聚体POT 1-TPP 1蛋白，其结合端粒单链DNA尾。TPP 1与将端粒酶募集到端粒和刺激端粒酶持续合成能力（在单个引物结合事件后添加多个DNA重复序列）有关。确定这些活动的机制一直很困难，特别是因为遗传扰动也往往会影响TPP 1的基本染色体末端保护功能。在这里，我们确定分离的功能突变体的TPP 1保留完整的端粒帽功能在体外和体内，但有缺陷的结合端粒酶。这七个功能分离突变映射到TPP 1表面的一片氨基酸，即TEL片，它既将端粒酶招募到端粒，又促进高持续合成能力的DNA合成，这表明这两种活动是相同分子相互作用的表现。鉴于端粒酶和TPP 1之间的相互作用是体内端粒酶功能所必需的，TPP 1的TEL补丁为抗癌药物开发提供了新的靶点。
Human chromosome ends are capped by shelterin, a protein complex that protects the natural ends from being recognized as sites of DNA damage and also regulates the telomere-replicating enzyme, telomerase. Shelterin includes the heterodimeric POT1-TPP1 protein, which binds the telomeric single-stranded DNA tail. TPP1 has been implicated both in recruiting telomerase to telomeres and in stimulating telomerase processivity (the addition of multiple DNA repeats after a single primer-binding event). Determining the mechanisms of these activities has been difficult, especially because genetic perturbations also tend to affect the essential chromosome end-protection function of TPP1. Here we identify separation-of-function mutants of TPP1 that retain full telomere-capping function in vitro and in vivo, yet are defective in binding telomerase. The seven separation-of-function mutations map to a patch of amino acids on the surface of TPP1, the TEL patch, that both recruits telomerase to telomeres and promotes high-processivity DNA synthesis, indicating that these two activities are manifestations of the same molecular interaction. Given that the interaction between telomerase and TPP1 is required for telomerase function in vivo, the TEL patch of TPP1 provides a new target for anti-cancer drug development.
登录
查看更多内容
影响因子：
64.8
作者：
Park, Jae-Il;Venteicher, Andrew S.;Hong, Ji Yeon;Choi, Jinkuk;Jun, Sohee;Shkreli, Marina;Chang, Woody;Meng, Zhaojing;Cheung, Peggie;Ji, Hong;McLaughlin, Margaret;Veenstra, Timothy D.;Nusse, Roel;McCrea, Pierre D.;Artandi, Steven E.
通讯作者：
Artandi, Steven E.
影响因子：
64.8
作者：
Wang, Feng;Podell, Elaine R.;Lei, Ming
通讯作者：
Lei, Ming
影响因子：
21.3
作者：
Liu, D;Safari, A;Zhou, SY
通讯作者：
Zhou, SY
影响因子：
16
作者：
Mossessova, E;Lima, CD
通讯作者：
Lima, CD
影响因子：
56.9
作者：
Lingner, J;Hughes, TR;Cech, TR
通讯作者：
Cech, TR