The exoribonuclease XRN2 mediates degradation of the long non‐coding telomeric RNA TERRA
- 26 May 2023
- journal article
- research article
- Published by Wiley in FEBS Letters
- Vol. 597 (14), 1818-1836
- https://doi.org/10.1002/1873-3468.14639
Abstract
The telomeric repeat-containing RNA, TERRA, associates with both telomeric DNA and telomeric proteins, often forming RNA:DNA hybrids (R-loops). TERRA is most abundant in cancer cells utilizing the alternative lengthening of telomeres (ALT) pathway for telomere maintenance, suggesting that persistent TERRA R-loops may contribute to activation of the ALT mechanism. Therefore, we sought to identify the enzyme(s) that regulate TERRA metabolism in mammalian cells. Here, we identify that the 5 '-3 ' exoribonuclease XRN2 regulates the stability of TERRA RNA. Moreover, while stabilization of TERRA alone was insufficient to drive ALT, depletion of XRN2 in ALT-positive cells led to a significant increase in TERRA R-loops and exacerbated ALT activity. Together, our findings highlight XRN2 as a key determinant of TERRA metabolism and telomere stability in cancer cells that rely on the ALT pathway.Funding Information
- Clinical and Translational Science Institute, Boston University (1UL1TR001430)
- Genome Science Institute, Boston University
- Center for Scientific Review (R01CA201446, R01CA214880, R35GM146769)
- National Center for Advancing Translational Sciences
- National Institutes of Health
This publication has 70 references indexed in Scilit:
- R Loops: From Transcription Byproducts to Threats to Genome StabilityMolecular Cell, 2012
- Human telomeres replicate using chromosome-specific, rather than universal, replication programsThe Journal of cell biology, 2012
- Prevalence of the Alternative Lengthening of Telomeres Telomere Maintenance Mechanism in Human Cancer SubtypesThe American Journal of Pathology, 2011
- Altered Telomeres in Tumors with ATRX and DAXX MutationsScience, 2011
- Human Senataxin Resolves RNA/DNA Hybrids Formed at Transcriptional Pause Sites to Promote Xrn2-Dependent TerminationMolecular Cell, 2011
- TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNANature, 2011
- The human core exosome interacts with differentially localized processive RNases: hDIS3 and hDIS3LThe EMBO Journal, 2010
- Distinct Factors Control Histone Variant H3.3 Localization at Specific Genomic RegionsCell, 2010
- TERRA RNA Binding to TRF2 Facilitates Heterochromatin Formation and ORC Recruitment at TelomeresMolecular Cell, 2009
- Telomeres shorten during ageing of human fibroblastsNature, 1990