Arora Rajika, Lee Yongwoo, Wischnewski Harry, Brun Catherine M, Schwarz Tobias, Azzalin Claus M
Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ), Zürich CH-8093, Switzerland.
Nat Commun. 2014 Oct 21;5:5220. doi: 10.1038/ncomms6220.
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.
一部分癌细胞通过不依赖端粒酶的“端粒替代延长”（ALT）途径维持端粒长度。ALT依赖于端粒序列之间的同源重组（HR）；然而，是什么使得ALT端粒具有重组活性仍不清楚。在这里，我们表明RNA核酸内切酶RNaseH1调节端粒DNA与长链非编码RNA TERRA之间的RNA-DNA杂交体水平，并且是ALT细胞中端粒维持的关键介质。RNaseH1特异性地在ALT细胞中与端粒结合，其缺失导致端粒杂交体积累、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端粒的重组活性并导致端粒缩短。改变细胞中RNaseH1的水平不会扰乱端粒酶阳性细胞中的端粒稳态。RNaseH1维持ALT端粒处受调控的端粒RNA-DNA杂交体水平，以触发同源重组，同时又不会过于严重地损害端粒完整性。
