SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability

Genes Dev. 2017 Jul 1;31(13):1370-1381. doi: 10.1101/gad.300624.117. Epub 2017 Aug 8.


R loops are three-stranded nucleic acid structures consisting of an RNA:DNA heteroduplex and a "looped-out" nontemplate strand. As aberrant formation and persistence of R loops block transcription elongation and cause DNA damage, mechanisms that resolve R loops are essential for genome stability. Here we show that the DEAD (Asp-Glu-Ala-Asp)-box RNA helicase DDX21 efficiently unwinds R loops and that depletion of DDX21 leads to accumulation of cellular R loops and DNA damage. Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases. Knockdown of SIRT7 leads to the same phenotype as depletion of DDX21 (i.e., increased formation of R loops and DNA double-strand breaks), indicating that SIRT7 and DDX21 cooperate to prevent R-loop accumulation, thus safeguarding genome integrity. Moreover, DDX21 resolves estrogen-induced R loops on estrogen-responsive genes in breast cancer cells, which prevents the blocking of transcription elongation on these genes.

Keywords: DDX21 helicase; DNA damage; R loops; SIRT7; acetylation; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • DNA / chemistry
  • DNA / genetics
  • DNA Damage / genetics
  • DNA Helicases / metabolism
  • DNA Repair / genetics
  • DNA-Directed RNA Polymerases / metabolism
  • Enzyme Activation
  • Gene Knockdown Techniques
  • Genomic Instability / genetics*
  • HEK293 Cells
  • Humans
  • MCF-7 Cells
  • Nucleic Acid Conformation*
  • Sirtuins / genetics
  • Sirtuins / metabolism*


  • SIRT7 protein, human
  • DNA
  • DNA-Directed RNA Polymerases
  • Sirtuins
  • DDX21 protein, human
  • DNA Helicases
  • DEAD-box RNA Helicases