caa a22 4500 528786253 20190713030956.0 cr unu---uuuuu 180924s2014 xx s 000 0 eng 10.3929/ethz-b-000094497 doi 10.1038/ncomms6220 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/94497 RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells [Elektronische Daten] [Rajika Arora, Yongwoo Lee, Harry Wischnewski, Catherine M. Brun, Tobias Schwarz, Claus M. Azzalin] Nat Commun Open access ethresearch 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. Creative Commons Attribution 4.0 International http://creativecommons.org/licenses/by/4.0 ethresearch Arora Rajika joint author Lee Yongwoo joint author Wischnewski Harry joint author Brun Catherine M. joint author Schwarz Tobias joint author Azzalin Claus M. joint author Nature Communications London : Nature Publishing Group 5, p. 5220 2041-1723 http://hdl.handle.net/20.500.11850/94497 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/94497 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- Arora Rajika joint author ETHRESEARCH 700 1- Lee Yongwoo joint author ETHRESEARCH 700 1- Wischnewski Harry joint author ETHRESEARCH 700 1- Brun Catherine M. joint author ETHRESEARCH 700 1- Schwarz Tobias joint author ETHRESEARCH 700 1- Azzalin Claus M. joint author ETHRESEARCH 773 0- Nature Communications London : Nature Publishing Group 5, p. 5220 2041-1723 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access