Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks

Nat Cell Biol. 2017 Dec;19(12):1400-1411. doi: 10.1038/ncb3643. Epub 2017 Nov 27.


The DNA damage response (DDR) preserves genomic integrity. Small non-coding RNAs termed DDRNAs are generated at DNA double-strand breaks (DSBs) and are critical for DDR activation. Here we show that active DDRNAs specifically localize to their damaged homologous genomic sites in a transcription-dependent manner. Following DNA damage, RNA polymerase II (RNAPII) binds to the MRE11-RAD50-NBS1 complex, is recruited to DSBs and synthesizes damage-induced long non-coding RNAs (dilncRNAs) from and towards DNA ends. DilncRNAs act both as DDRNA precursors and by recruiting DDRNAs through RNA-RNA pairing. Together, dilncRNAs and DDRNAs fuel DDR focus formation and associate with 53BP1. Accordingly, inhibition of RNAPII prevents DDRNA recruitment, DDR activation and DNA repair. Antisense oligonucleotides matching dilncRNAs and DDRNAs impair site-specific DDR focus formation and DNA repair. We propose that DDR signalling sites, in addition to sharing a common pool of proteins, individually host a unique set of site-specific RNAs necessary for DDR activation.

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Acid Anhydride Hydrolases
  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell-Free System
  • DNA Breaks, Double-Stranded*
  • DNA Damage* / genetics
  • DNA Damage* / physiology
  • DNA Repair* / genetics
  • DNA Repair* / physiology
  • DNA-Binding Proteins
  • MRE11 Homologue Protein / metabolism
  • Mice
  • Models, Biological
  • Nuclear Proteins / metabolism
  • Oligonucleotides, Antisense / genetics
  • RNA Polymerase II / metabolism
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Transcription, Genetic
  • Tumor Suppressor p53-Binding Protein 1 / metabolism


  • ATP-Binding Cassette Transporters
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Mre11a protein, mouse
  • Nijmegen breakage syndrome 1 protein, mouse
  • Nuclear Proteins
  • Oligonucleotides, Antisense
  • RNA, Long Noncoding
  • Trp53bp1 protein, mouse
  • Tumor Suppressor p53-Binding Protein 1
  • RNA Polymerase II
  • MRE11 Homologue Protein
  • Acid Anhydride Hydrolases
  • Rad50 protein, mouse