STING protects breast cancer cells from intrinsic and genotoxic-induced DNA instability via a non-canonical, cell-autonomous pathway

Cheradame, Laura; Guerrera, Chiara; Gaston, Julie; Schmitt, Alain; Jung, Vincent; Pouillard, Marion; Radosevic‐Robin, Nina; Modesti, Mauro; Judde, Jean-Gabriel; Cairo, Stefano; Goffin, Vincent

doi:10.1038/s41388-021-02037-4

Cited by 31 publications

(24 citation statements)

References 84 publications

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“…STING has been confirmed to promote DDR and enable cell survival without cGAS, though they are partners ( Cheradame et al, 2021 ). Downregulation of STING increases cell death and makes breast cancer cells more sensitive to genotoxic treatment.…”

Section: The Impacts Of Nucleic Acid-sensing Pathways On Dna Repairmentioning

confidence: 99%

Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy

Xie

Luo

2022

Front. Cell Dev. Biol.

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The repair of DNA damage is a complex process, which helps to maintain genome fidelity, and the ability of cancer cells to repair therapeutically DNA damage induced by clinical treatments will affect the therapeutic efficacy. In the past decade, great success has been achieved by targeting the DNA repair network in tumors. Recent studies suggest that DNA damage impacts cellular innate and adaptive immune responses through nucleic acid-sensing pathways, which play essential roles in the efficacy of DNA repair targeted therapy. In this review, we summarize the current understanding of the molecular mechanism of innate immune response triggered by DNA damage through nucleic acid-sensing pathways, including DNA sensing via the cyclic GMP-AMP synthase (cGAS), Toll-like receptor 9 (TLR9), absent in melanoma 2 (AIM2), DNA-dependent protein kinase (DNA-PK), and Mre11-Rad50-Nbs1 complex (MRN) complex, and RNA sensing via the TLR3/7/8 and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). Furthermore, we will focus on the recent developments in the impacts of nucleic acid-sensing pathways on the DNA damage response (DDR). Elucidating the DDR-immune response interplay will be critical to harness immunomodulatory effects to improve the efficacy of antitumor immunity therapeutic strategies and build future therapeutic approaches.

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Section: The Impacts Of Nucleic Acid-sensing Pathways On Dna Repairmentioning

confidence: 99%

Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy

Xie

Luo

2022

Front. Cell Dev. Biol.

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“…In fact, the nuclear STING1 was originally identified by a proteomics study of the nuclear envelope, and this finding is supported by two subsequent studies, which show a role for nuclear STING1 in promoting chromatin compaction through epigenetic modifications ( 86 – 88 ). STING1 can bind the DNA-dependent protein kinase (DNA-PK) complex in the inner nuclear membrane, which protects breast cancer cells from DNA instability by promoting DDR in a CGAS-independent manner ( 14 ). Nuclear STING1 also interacts with various nucleotide-binding proteins, which regulate gene transcription of type I IFNs ( 89 ).…”

Section: Roles Of Sting1 In Organellesmentioning

confidence: 99%

“…STING1 redistributes from the nucleus to the ER, increasing both dsDNA- and dsRNA-triggered immune responses. In addition, subcellular localization analysis and the nuclear interactome show that STING1 co-localizes with the lamina, which serves as an anchoring point for chromatin and transcription factors and interacts with transcriptional activators and co-activators ( 14 , 89 ), indicating that nuclear STING1 may be directly involved in the regulation of gene transcriptional activity ( Figure 2 ).…”

Section: Roles Of Sting1 In Organellesmentioning

confidence: 99%

“…Accumulating evidence demonstrates that the subcellular distribution of STING1 is not restricted to an ER-to-Golgi apparatus (Golgi) membranous network. Under different circumstances, the localization on other organelles enables some immune-independent functions of STING1, contributing to autophagy ( 10 ), regulated cell death ( 11 ), ER stress ( 12 ), lipid metabolism ( 13 ), and DNA damage response (DDR) ( 14 ). The participation and crosstalk of these organelles determine the function of STING1 in diseases by controlling its location, binding partners, and signaling recognition.…”

Section: Introductionmentioning

confidence: 99%

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STING1 in Different Organelles: Location Dictates Function

2022

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Stimulator of interferon response cGAMP interactor 1 (STING1), also known as TMEM173, is an immune adaptor protein that governs signal crosstalk that is implicated in many physiological and pathological processes. Although it has been established that STING1 traffics from the endoplasmic reticulum (ER) to Golgi apparatus (Golgi) upon DNA-triggered activation, emerging evidence reveals that STING1 can be transported to different organelles, which dictate its immune-dependent (e.g., the production of type I interferons and pro-inflammatory cytokines) and -independent (e.g., the activation of autophagy and cell death) functions. In this brief review, we outline the roles of STING1 in different organelles (including the ER, ER-Golgi intermediate compartment, Golgi, mitochondria, endosomes, lysosomes, and nucleus) and discuss the potential relevance of these roles to diseases and pharmacological interventions.

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“…In a systematic profiling study, DNA-PKcs directly phosphorylated the DNA sensor IFI16 and promoted IFI16-driven cytokine responses ( 89 ). Furthermore, regardless of its partner cGAS, STING can localize to the inner nuclear membrane in breast cancer tumor samples and promote cancer cell survival by resistance to DNA-damaging agents through interacting with DNA-PK ( 95 ). Therefore, further studies are warranted to better understand mechanisms governing DNA-PK substrate selection within the context of the innate immune response.…”

Section: Ddr In Innate Immunitymentioning

confidence: 99%

Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy

Yin

Lees‐Miller

et al. 2021

Front. Immunol.

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The DNA damage response (DDR) is an organized network of multiple interwoven components evolved to repair damaged DNA and maintain genome fidelity. Conceptually the DDR includes damage sensors, transducer kinases, and effectors to maintain genomic stability and accurate transmission of genetic information. We have recently gained a substantially improved molecular and mechanistic understanding of how DDR components are interconnected to inflammatory and immune responses to stress. DDR shapes both innate and adaptive immune pathways: (i) in the context of innate immunity, DDR components mainly enhance cytosolic DNA sensing and its downstream STimulator of INterferon Genes (STING)-dependent signaling; (ii) in the context of adaptive immunity, the DDR is needed for the assembly and diversification of antigen receptor genes that is requisite for T and B lymphocyte development. Imbalances between DNA damage and repair impair tissue homeostasis and lead to replication and transcription stress, mutation accumulation, and even cell death. These impacts from DDR defects can then drive tumorigenesis, secretion of inflammatory cytokines, and aberrant immune responses. Yet, DDR deficiency or inhibition can also directly enhance innate immune responses. Furthermore, DDR defects plus the higher mutation load in tumor cells synergistically produce primarily tumor-specific neoantigens, which are powerfully targeted in cancer immunotherapy by employing immune checkpoint inhibitors to amplify immune responses. Thus, elucidating DDR-immune response interplay may provide critical connections for harnessing immunomodulatory effects plus targeted inhibition to improve efficacy of radiation and chemotherapies, of immune checkpoint blockade, and of combined therapeutic strategies.

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STING protects breast cancer cells from intrinsic and genotoxic-induced DNA instability via a non-canonical, cell-autonomous pathway

Cited by 31 publications

References 84 publications

Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy

Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy

STING1 in Different Organelles: Location Dictates Function

Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy

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