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TERRA R-loops trigger a switch in telomere maintenance towards break-induced replication and PRIMPOL-dependent

Suna In1, Patricia Renck Nunes1,2, Rita Valador Fernandes1,3

  • 1Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, 1015, Switzerland.

The EMBO Journal
|July 7, 2025
PubMed
Summary
This summary is machine-generated.

TERRA long noncoding RNAs form R-loops at telomeres, requiring RAD51 and RAD51AP1. These R-loops promote telomere maintenance via break-induced replication (BIR) and PRIMPOL-dependent repair, crucial for ALT cancer cell survival.

Keywords:
Break-induced ReplicationPRIMPOLR-loopsTERRATelomeres

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Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Telomeres are crucial for chromosome stability and are maintained by telomerase or alternative lengthening of telomeres (ALT).
  • TERRA (Telomeric Repeat-containing RNA) long noncoding RNAs are implicated in telomere maintenance but their precise functions are unclear.
  • R-loops, DNA:RNA hybrids, form at telomeres and may play a role in TERRA-mediated regulation.

Purpose of the Study:

  • To investigate the mechanisms by which TERRA long noncoding RNAs regulate telomere maintenance.
  • To determine the role of RAD51, RAD51AP1, and PRIMPOL in TERRA R-loop formation and telomere repair.
  • To elucidate how TERRA R-loops influence DNA replication and repair pathways in ALT cancer cells.

Main Methods:

  • Induction of TERRA transcription and R-loop formation in telomerase-expressing cells.
  • Assessing the requirement of RAD51 and RAD51AP1 for TERRA R-loop formation.
  • Investigating the impact of TERRA R-loops on DNA replication using semiconservative DNA replication assays.
  • Analyzing the role of PRIMPOL in DNA repair and telomere maintenance.
  • Evaluating synthetic lethality between PRIMPOL depletion and BIR deficiency in U2OS ALT cancer cells.

Main Results:

  • TERRA R-loop formation requires the non-redundant functions of RAD51 and RAD51AP1.
  • TERRA R-loops impede semiconservative DNA replication, promoting telomere maintenance through homology-directed repair (HDR) via break-induced replication (BIR).
  • TERRA induces PRIMPOL-dependent repair, which initiates DNA synthesis downstream of replication obstacles, acting in parallel to BIR for telomere maintenance and cell survival.
  • PRIMPOL depletion exhibits synthetic lethality with BIR deficiency in U2OS ALT cancer cells.
  • TERRA R-loops alone are sufficient to trigger ALT-typical telomere repair mechanisms without other hallmark ALT chromatin changes.

Conclusions:

  • TERRA R-loops are key mediators of telomere maintenance in ALT cancer cells.
  • The RAD51/RAD51AP1 complex is essential for TERRA R-loop formation.
  • TERRA R-loops engage BIR and PRIMPOL-dependent repair pathways to ensure telomere stability and cancer cell survival.
  • TERRA-induced R-loops represent a novel therapeutic vulnerability in ALT cancer.