RAD51 interconnects between DNA replication, DNA repair and immunity

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.

Identification of Key Genes Related to Lung Squamous Cell Carcinoma Using Bioinformatics Analysis

“…RAD51 is the central protein in the homologous recombination (HR) pathway and is critical for DNA replication and repair. Recent studies have reported that RAD51 is also implicated in the suppression of innate immunity [46]. Hu et al pointed out that RAD51 expression was elevated by a KRAS mutation which predominantly occurred in lung adenocarcinomas.…”

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

“…A cell line derived from an ATLD patient containing an MRE11 mutation that abrogates its DNA binding properties has defects in IFN production (198). Interestingly, RAD51 absence can also induce an innate response (199). RAD51 protects DNA inside the nucleus from MRE11-mediated nucleolytic degradation.…”

Molecular and physiological consequences of faulty eukaryotic ribonucleotide excision repair

“…The involvement of cytoplasmic DNA in AGS etiology is further highlighted by the role of the exonuclease TREX1, another gene frequently mutated in AGS patients. In line with this, depletion of RAD51 in both murine and human cell lines increases IFN signaling upon irradiating DNA damage (Bhattacharya et al, 2017). The accumulation of ssDNA in the absence of TREX1 leads to an exhaustion of RAD51 and RPA, which in turn directly contributes to the generation of replication stress and p53-dependent checkpoint signaling in addition to the activation of a cGAS-STING-mediated IFN response (Fig 5B).…”

“…The accumulation of ssDNA in the absence of TREX1 leads to an exhaustion of RAD51 and RPA, which in turn directly contributes to the generation of replication stress and p53-dependent checkpoint signaling in addition to the activation of a cGAS-STING-mediated IFN response ( Fig 5B). In line with this, depletion of RAD51 in both murine and human cell lines increases IFN signaling upon irradiating DNA damage (Bhattacharya et al, 2017). This suggests that the release of self-derived DNA into the cytoplasm is a general phenomenon during DNA replication stress and is counteracted by mechanisms acting both at the stalled replication fork and in the cytoplasm.…”