Regulation of the Cell-Intrinsic DNA Damage Response by the Innate Immune Machinery

Abstract

Maintenance of genomic integrity is crucial for cell survival. As such, elegant DNA damage response (DDR) systems have evolved to ensure proper repair of DNA double-strand breaks (DSBs) and other lesions that threaten genomic integrity. Towards this end, most therapeutic studies have focused on understanding of the canonical DNA DSB repair pathways to enhance the efficacy of DNA-damaging therapies. While these approaches have been fruitful, there has been relatively limited success to date and potential for significant normal tissue toxicity. With the advent of novel immunotherapies, there has been interest in understanding the interactions of radiation therapy with the innate and adaptive immune responses, with the ultimate goal of enhancing treatment efficacy. While a substantial body of work has demonstrated control of the immune-mediated (extrinsic) responses to DNA-damaging therapies by several innate immune pathways (e.g., cGAS–STING and RIG-I), emerging work demonstrates an underappreciated role of the innate immune machinery in directly regulating tumor cell-intrinsic/cell-autonomous responses to DNA damage.

Alphaherpesvirus upregulates NDRG1 expression to facilitate the nuclear import of viral UL31 and UL34 proteins

“…42 Furthermore, DDR can trigger an innate immune response that inhibits viral proliferation. 26,43 Therefore, further investigations into the role of DDR in alphaherpesvirus proliferation are needed to identify potentially therapeutic targets.…”

“…However, it has been reported that H2AX phosphorylation and DNA damage kinase activity are dispensable for HSV‐1 replication 42 . Furthermore, DDR can trigger an innate immune response that inhibits viral proliferation 26,43 . Therefore, further investigations into the role of DDR in alphaherpesvirus proliferation are needed to identify potentially therapeutic targets.…”

Regulation of the Innate Immune Response during the Human Papillomavirus Life Cycle

“…Overexpression of the HPV18 and HPV16 E2 proteins is also sufficient to downregulate STING mRNA levels along with the several other innate immune genes [95,99]. The cGAS-STING pathway plays a critical role in the response to damaged DNA that is mislocalized to the cytoplasm as well as DNA within micronuclei [100,101]. HR HPVs induce DNA damage and require activation of DNA damage response pathways for viral replication [14,25].…”

MicroRNAs and Drug Resistance in Non-Small Cell Lung Cancer: Where Are We Now and Where Are We Going

“…Radiotherapy is an important component of the multi-modality treatment for metastatic NSCLC, with ~50% of NSCLC patients undergoing radiotherapy either for a curative or palliative intent [ 105 ]. Radiotherapy kills tumor cells either by directly inducing DNA damage, which leads to cell death as well as increases anti-tumor immune response [ 106 ] or by indirectly altering tumor vasculature [ 107 ]. As said before, a large fraction of miRNAs associated with radiotherapy was downregulated in radioresistant samples and vice versa upregulated in radiosensitive ones, for example:(i) miR-218-5p overexpression restored the sensitivity of radiation-resistant cells through direct regulation of PRKDC, a member of the non-homologous end-joining pathway in the DNA double-strand break repair response [ 108 ]; (ii) rescue of miR-126-3p expression increased radiation-induced apoptosis by inactivation of the PI3K/AKT signaling [ 109 ].…”