RAD51 interconnects between DNA replication, DNA repair and immunity.
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.
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Souparno
S
Bhattacharya
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Kalayarasan
K
Srinivasan
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Salim
S
Abdisalaam
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Fengtao
F
Su
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Prithvi
P
Raj
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Igor
I
Dozmorov
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Ritu
R
Mishra
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Edward K
EK
Wakeland
Department of Molecular Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Subroto
S
Ghose
Department of Molecular Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Shibani
S
Mukherjee
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Aroumougame
A
Asaithamby
D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics* / Q000276:immunology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D017930:Genes, Reporter; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007113:Immunity, Innate; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D000076228:MRE11 Homologue Protein; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D011744:Pyrimidinones / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D059767:Recombinational DNA Repair / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013871:Thiones / Q000494:pharmacology; D000077337:Vorinostat; D000097573:Red Fluorescent Protein; D000099197:STING Protein
D004247:DNA; D004268:DNA-Binding Proteins; D006877:Hydroxamic Acids; D008164:Luminescent Proteins; D000076228:MRE11 Homologue Protein; D008565:Membrane Proteins; D011744:Pyrimidinones; D051135:Rad51 Recombinase; D013871:Thiones; D000077337:Vorinostat; D000097573:Red Fluorescent Protein; C526365:6-(4-hydroxyphenyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone; C121766:MRE11 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C495153:RAD51 protein, human