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RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells.

  • Arora R Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ), Zürich CH-8093, Switzerland.
  • Lee Y Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ), Zürich CH-8093, Switzerland.
  • Wischnewski H Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ), Zürich CH-8093, Switzerland.
  • Brun CM Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ), Zürich CH-8093, Switzerland.
  • Schwarz T Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ), Zürich CH-8093, Switzerland.
  • Azzalin CM Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich (ETHZ), Zürich CH-8093, Switzerland.
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  • 2014-10-22
Published in:
  • Nature communications. - 2014
Cell Line, Tumor
DNA
DNA, Single-Stranded
Endonucleases
Gene Expression Regulation, Neoplastic
HEK293 Cells
HeLa Cells
Homeostasis
Homologous Recombination
Humans
Imaging, Three-Dimensional
In Situ Hybridization, Fluorescence
Nucleic Acids
RNA, Small Interfering
Recombination, Genetic
Replication Protein A
Ribonuclease H
Telomerase
Telomere
Telomere Shortening
English 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.
Language
  • English
Open access status
hybrid
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Persistent URL
https://folia.unifr.ch/global/documents/153447
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