Affiliation:
1. Departments of Pharmacology, Physiology & Biophysics and Medicine, Cancer Center Boston University Chobanian & Avedisian School of Medicine MA Boston USA
2. Departments of Biochemistry and Cell Biology Boston University Chobanian & Avedisian School of Medicine MA USA
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.
Funder
Clinical and Translational Science Institute, Boston University
Genome Science Institute, Boston University
Center for Scientific Review
National Center for Advancing Translational Sciences
National Institutes of Health
Subject
Cell Biology,Genetics,Molecular Biology,Biochemistry,Structural Biology,Biophysics
Cited by
3 articles.
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