RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells.
RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells.
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DOI：
10.1038/ncomms6220
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发表时间：
2014-10-21
影响因子：
16.6
通讯作者：
Azzalin, Claus M.
中科院分区：
文献类型：
--
作者：
Arora, Rajika;Lee, Yongwoo;Wischnewski, Harry;Brun, Catherine M.;Schwarz, Tobias;Azzalin, Claus M.
一部分癌细胞通过不依赖端粒酶的“端粒替代延长”（ALT）途径维持端粒。ALT依赖端粒序列之间的同源重组（HR）；然而，是什么使ALT端粒具有重组活性仍不清楚。在此我们表明，RNA内切酶RNaseH1调节端粒DNA与长链非编码RNA TERRA之间的RNA - DNA杂合体水平，并且是ALT细胞中端粒维持的关键介质。RNaseH1特异性地与ALT细胞中的端粒相关联，其缺失导致端粒杂合体积累、单链端粒DNA暴露、端粒处复制蛋白A激活以及端粒突然切除。相反，RNaseH1的过表达削弱了ALT端粒的重组特性并导致端粒缩短。改变细胞中RNaseH1的水平不会干扰端粒酶阳性细胞中的端粒稳态。RNaseH1在ALT端粒处维持端粒RNA - DNA杂合体的调节水平，以触发同源重组，同时不会过于严重地损害端粒完整性。
一部分癌症通过激活端粒替代延长（ALT）途径不依赖端粒酶维持端粒长度。在此作者表明RNaseH1通过调节TERRA与端粒DNA之间的RNA - DNA杂合体水平来调节ALT细胞中端粒的同源重组频率。
A fraction of cancer cells maintain telomeres through the telomerase-independent, ‘Alternative Lengthening of Telomeres’ (ALT) pathway. ALT relies on homologous recombination (HR) between telomeric sequences; yet, what makes ALT telomeres recombinogenic remains unclear. Here we show that the RNA endonuclease RNaseH1 regulates the levels of RNA–DNA hybrids between telomeric DNA and the long noncoding RNA TERRA, and is a key mediator of telomere maintenance in ALT cells. RNaseH1 associated to telomeres specifically in ALT cells and its depletion led to telomeric hybrid accumulation, exposure of single-stranded telomeric DNA, activation of replication protein A at telomeres and abrupt telomere excision. Conversely, overexpression of RNaseH1 weakened the recombinogenic nature of ALT telomeres and led to telomere shortening. Altering cellular RNaseH1 levels did not perturb telomere homoeostasis in telomerase-positive cells. RNaseH1 maintains regulated levels of telomeric RNA–DNA hybrids at ALT telomeres to trigger HR without compromising telomere integrity too severely. A subset of cancers maintains telomere length independently of telomerase by activating alternative lengthening of telomeres (ALT) pathways. Here the authors show that RNaseH1 modulates telomeric homologous recombination frequencies in ALT cells by regulating the levels of RNA–DNA hybrids between TERRA and telomeric DNA.
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影响因子：
64.5
作者：
Hu J;Hwang SS;Liesa M;Gan B;Sahin E;Jaskelioff M;Ding Z;Ying H;Boutin AT;Zhang H;Johnson S;Ivanova E;Kost-Alimova M;Protopopov A;Wang YA;Shirihai OS;Chin L;DePinho RA
通讯作者：
DePinho RA
影响因子：
4.5
作者：
Nergadze, Solomon G.;Farnung, Benjamin O.;Azzalin, Claus M.
通讯作者：
Azzalin, Claus M.
影响因子：
5.3
作者：
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通讯作者：
Hess, Jay L.
影响因子：
56.9
作者：
Azzalin, Claus M.;Reichenbach, Patrick;Lingner, Joachim
通讯作者：
Lingner, Joachim
影响因子：
4.7
作者：
Conomos D;Pickett HA;Reddel RR
通讯作者：
Reddel RR