Abstract
The RNA-sensing pathway contributes to type I interferon (IFN) production induced by DNA damaging agents. However, the potential involvement of RNA sensors in DNA repair is unknown. Here, we found that retinoic acid-inducible gene I (RIG-I), a key cytosolic RNA sensor that recognizes RNA virus and initiates the MAVS-IRF3-type I IFN signaling cascade, is recruited to double-stranded breaks (DSBs) and suppresses non-homologous end joining (NHEJ). Mechanistically, RIG-I interacts with XRCC4, and the RIG-I/XRCC4 interaction impedes the formation of XRCC4/LIG4/XLF complex at DSBs. High expression of RIG-I compromises DNA repair and sensitizes cancer cells to irradiation treatment. In contrast, depletion of RIG-I renders cells resistant to irradiation in vitro and in vivo. In addition, this mechanism suggests a protective role of RIG-I in hindering retrovirus integration into the host genome by suppressing the NHEJ pathway. Reciprocally, XRCC4, while suppressed for its DNA repair function, has a critical role in RIG-I immune signaling through RIG-I interaction. XRCC4 promotes RIG-I signaling by enhancing oligomerization and ubiquitination of RIG-I, thereby suppressing RNA virus replication in host cells. In vivo, silencing XRCC4 in mouse lung promotes influenza virus replication in mice and these mice display faster body weight loss, poorer survival, and a greater degree of lung injury caused by influenza virus infection. This reciprocal regulation of RIG-I and XRCC4 reveals a new function of RIG-I in suppressing DNA repair and virus integration into the host genome, and meanwhile endues XRCC4 with a crucial role in potentiating innate immune response, thereby helping host to prevail in the battle against virus.
Highlights
The RNA-sensing pathway contributes to type I interferon (IFN) production induced by DNA damaging agents
We found that retinoic acid-inducible gene I (RIG-I) hinders retrovirus integration into the host genome by suppressing non-homologous end joining (NHEJ) pathway, which is distinguished from its canonical role in suppressing RNA virus infection by initiating innate immune response
We found that re-overexpression of wild type (WT), but not the XRCC4 mutant devoid of interaction with RIG-I, could reverse the insufficient oligomerization of RIG-I and impaired interaction of RIG-I and mitochondrial antiviral-signaling protein (MAVS) caused by loss of XRCC4 (Fig. 5f, h), indicating that XRCC4 contributes to RIG-I signaling by interacting with RIG-I and promoting oligomerization and ubiquitination of RIG-I
Summary
The RNA-sensing pathway contributes to type I interferon (IFN) production induced by DNA damaging agents. We found that retinoic acid-inducible gene I (RIG-I), a key cytosolic RNA sensor that recognizes RNA virus and initiates the MAVS-IRF3-type I IFN signaling cascade, is recruited to double-stranded breaks (DSBs) and suppresses non-homologous end joining (NHEJ). In vivo, silencing XRCC4 in mouse lung promotes influenza virus replication in mice and these mice display faster body weight loss, poorer survival, and a greater degree of lung injury caused by influenza virus infection This reciprocal regulation of RIG-I and XRCC4 reveals a new function of RIG-I in suppressing DNA repair and virus integration into the host genome, and endues XRCC4 with a crucial role in potentiating innate immune response, thereby helping host to prevail in the battle against virus. Whether RNA sensors are involved in DNA repair is unknown
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