The Exoribonuclease XRN2 Mediates Degradation of the Long Non-coding Telomeric RNA TERRA

Overview

Journal FEBS Lett

Specialty Biochemistry

Date 2023 May 16

PMID 37191774

Authors

Matthew Reiss

Joshua Keegan

Anne Aldrich

Shawn M Lyons

Rachel Litman Flynn

Affiliations

Soon will be listed here.

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.

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