RAD51 interconnects between DNA replication, DNA repair and immunity

Nucleic Acids Res. 2017 May 5;45(8):4590-4605. doi: 10.1093/nar/gkx126.

Abstract

RAD51, a multifunctional protein, plays a central role in DNA replication and homologous recombination repair, and is known to be involved in cancer development. We identified a novel role for RAD51 in innate immune response signaling. Defects in RAD51 lead to the accumulation of self-DNA in the cytoplasm, triggering a STING-mediated innate immune response after replication stress and DNA damage. In the absence of RAD51, the unprotected newly replicated genome is degraded by the exonuclease activity of MRE11, and the fragmented nascent DNA accumulates in the cytosol, initiating an innate immune response. Our data suggest that in addition to playing roles in homologous recombination-mediated DNA double-strand break repair and replication fork processing, RAD51 is also implicated in the suppression of innate immunity. Thus, our study reveals a previously uncharacterized role of RAD51 in initiating immune signaling, placing it at the hub of new interconnections between DNA replication, DNA repair, and immunity.

MeSH terms

  • Cell Line, Tumor
  • DNA / genetics*
  • DNA / immunology
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Replication*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / immunology
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / immunology
  • Genes, Reporter
  • Humans
  • Hydroxamic Acids / pharmacology
  • Immunity, Innate
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • MRE11 Homologue Protein
  • Membrane Proteins / genetics*
  • Membrane Proteins / immunology
  • Pyrimidinones / pharmacology
  • Rad51 Recombinase / deficiency
  • Rad51 Recombinase / genetics*
  • Rad51 Recombinase / immunology
  • Recombinational DNA Repair / genetics*
  • Recombinational DNA Repair / immunology
  • Red Fluorescent Protein
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Thiones / pharmacology
  • Vorinostat

Substances

  • 6-(4-hydroxyphenyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone
  • DNA-Binding Proteins
  • Hydroxamic Acids
  • Luminescent Proteins
  • MRE11 protein, human
  • Membrane Proteins
  • Pyrimidinones
  • STING1 protein, human
  • Thiones
  • Vorinostat
  • DNA
  • RAD51 protein, human
  • Rad51 Recombinase
  • MRE11 Homologue Protein