XRN2 Links Transcription Termination to DNA Damage and Replication Stress

PLoS Genet. 2016 Jul 20;12(7):e1006107. doi: 10.1371/journal.pgen.1006107. eCollection 2016 Jul.


XRN2 is a 5'-3' exoribonuclease implicated in transcription termination. Here we demonstrate an unexpected role for XRN2 in the DNA damage response involving resolution of R-loop structures and prevention of DNA double-strand breaks (DSBs). We show that XRN2 undergoes DNA damage-inducible nuclear re-localization, co-localizing with 53BP1 and R loops, in a transcription and R-loop-dependent process. XRN2 loss leads to increased R loops, genomic instability, replication stress, DSBs and hypersensitivity of cells to various DNA damaging agents. We demonstrate that the DSBs that arise with XRN2 loss occur at transcriptional pause sites. XRN2-deficient cells also exhibited an R-loop- and transcription-dependent delay in DSB repair after ionizing radiation, suggesting a novel role for XRN2 in R-loop resolution, suppression of replication stress, and maintenance of genomic stability. Our study highlights the importance of regulating transcription-related activities as a critical component in maintaining genetic stability.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / chemistry
  • Cell Nucleus / metabolism
  • DNA Damage*
  • DNA Helicases
  • DNA Repair
  • DNA Replication*
  • Exoribonucleases / genetics*
  • Exoribonucleases / physiology*
  • Gene Expression Regulation, Neoplastic
  • Genomic Instability
  • Genomics
  • HeLa Cells
  • Humans
  • Microscopy, Fluorescence
  • Multifunctional Enzymes
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Plasmids / metabolism
  • RNA Helicases / metabolism
  • RNA, Small Interfering / metabolism
  • Transcription, Genetic*
  • Tumor Suppressor p53-Binding Protein 1 / genetics*


  • Antineoplastic Agents
  • Multifunctional Enzymes
  • RNA, Small Interfering
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Exoribonucleases
  • XRN2 protein, human
  • SETX protein, human
  • DNA Helicases
  • RNA Helicases