RTEL1 influences the abundance and localization of TERRA RNA

Fiorella Ghisays, Aitor Garzia, Hexiao Wang, Claudia Canasto-Chibuque, Marcel Hohl, Sharon A. Savage, Thomas Tuschl and John H. J. Petrini ()
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Fiorella Ghisays: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center
Aitor Garzia: The Rockefeller University
Hexiao Wang: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center
Claudia Canasto-Chibuque: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center
Marcel Hohl: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center
Sharon A. Savage: National Cancer Institute
Thomas Tuschl: The Rockefeller University
John H. J. Petrini: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Telomere repeat containing RNAs (TERRAs) are a family of long non-coding RNAs transcribed from the subtelomeric regions of eukaryotic chromosomes. TERRA transcripts can form R-loops at chromosome ends; however the importance of these structures or the regulation of TERRA expression and retention in telomeric R-loops remain unclear. Here, we show that the RTEL1 (Regulator of Telomere Length 1) helicase influences the abundance and localization of TERRA in human cells. Depletion of RTEL1 leads to increased levels of TERRA RNA while reducing TERRA-containing R loops at telomeres. In vitro, RTEL1 shows a strong preference for binding G-quadruplex structures which form in TERRA. This binding is mediated by the C-terminal region of RTEL1, and is independent of the RTEL1 helicase domain. RTEL1 binding to TERRA appears to be essential for cell viability, underscoring the importance of this function. Degradation of TERRA-containing R-loops by overexpression of RNAse H1 partially recapitulates the increased TERRA levels and telomeric instability associated with RTEL1 deficiency. Collectively, these data suggest that regulation of TERRA is a key function of the RTEL1 helicase, and that loss of that function may contribute to the disease phenotypes of patients with RTEL1 mutations.

Date: 2021
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DOI: 10.1038/s41467-021-23299-2

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