PT  - JOURNAL ARTICLE
AU  - Fiorella Ghisays
AU  - Aitor Garzia
AU  - Hexiao Wang
AU  - Claudia Canasto-Chibuque
AU  - Marcel Hohl
AU  - Sharon A. Savage
AU  - Thomas Tuschl
AU  - John H. J. Petrini
TI  - RTEL1 Influences the Abundance and Localization of TERRA RNA
AID  - 10.1101/2020.05.12.088583
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.12.088583
4099  - http://biorxiv.org/content/early/2020/05/14/2020.05.12.088583.short
4100  - http://biorxiv.org/content/early/2020/05/14/2020.05.12.088583.full
AB  - Telomere repeat containing RNAs (TERRAs) are a family of long non-coding RNAs transcribed from the sub-telomeric 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 at the telomeres 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.Competing Interest StatementJ.H.J.P is a consultant for Novus Biologicals and ATROPOS Therapeutics, which are not competing interests with this study.