ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation

Hu, Mengjie; Zhou, Min; Bao, Xiaoyong; Pan, Dong; Jiao, Meng; Liu, Xinjian; Li, Fang; Li, Chuan-Yuan

doi:10.1172/jci139333

Cited by 148 publications

(144 citation statements)

References 62 publications

(57 reference statements)

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…To directly test the hypothesis of whether the eribulin-mediated release of mtDNA was indeed responsible for the increase in IFNβ expression, we took advantage of the fact that ethidium bromide (EtBr) depletes mtDNA while preserving mitochondria themselves (Armand et al, 2004). This method has been used by others to evaluate mtDNA-mediated activation of the cGAS-STING pathway (Hu et al, 2020;White et al, 2014;Yamazaki et al, 2020). We therefore cultured HCC1937 cells in EtBr for 5 days to generate mtDNA depleted (rho 0 ) HCC1937 cells as noted by the depletion of mitochondrial genes in these cells as compared to the untreated controls (Fig.…”

Section: Eribulin Activates the Cgas-sting Pathway By Inducing The Accumulation Of Cytoplasmic Mitochondrial Dnamentioning

confidence: 99%

Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA

et al. 2021

View full text Add to dashboard Cite

Section: Eribulin Activates the Cgas-sting Pathway By Inducing The Accumulation Of Cytoplasmic Mitochondrial Dnamentioning

confidence: 99%

Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA

et al. 2021

View full text Add to dashboard Cite

“…Together, downregulation of TFAM caused by ATM deficiency promotes leakage of mtDNA into the cytosol and thus activates the type 1 IFN system. These results also show that ATM, in addition to its function in DNA double strand repair, is indirectly involved in the stabilization of mtDNA and mitochondrial homeostasis(75). Hence, different subcellular localizations and functions of ATM are responsible for type I IFN induction and may lead to the autoimmune phenotype observed in this disease.The possible producer of DNA fragments during DNA repair, which further penetrate from the nucleus into the cytosol inducing a type I IFN response, was identified by Erdal et al: Liberated ssDNA fragments are excised by Bloom-helicase (BLM) and Exonuclease 1 (Exo1) in the "DNA end resection" of HR as mentioned above: BLM1/Exo1-deficient cells exhibited significant lower expression of ISGs after irradiation compared to wild type, indicating less liberation of ssDNA into the cytosol(14).…”

mentioning

confidence: 60%

“…mechanism was identified recently: ATM inhibition was shown to cause cytoplasmic leakage of mtDNA by downregulation of TFAM (mitochondrial transcription factor A), which is a mtDNA binding protein. Cytoplasmic mtDNA then activates cGAS-STING-dependent type I IFN secretion(75). Together, downregulation of TFAM caused by ATM deficiency promotes leakage of mtDNA into the cytosol and thus activates the type 1 IFN system.…”

mentioning

confidence: 99%

Type I Interferon Induction in Cutaneous DNA Damage Syndromes

Klein

Günther

2021

Front. Immunol.

View full text Add to dashboard Cite

Type I interferons (IFNs) as part of the innate immune system have an outstanding importance as antiviral defense cytokines that stimulate innate and adaptive immune responses. Upon sensing of pattern recognition particles (PRPs) such as nucleic acids, IFN secretion is activated and induces the expression of interferon stimulated genes (ISGs). Uncontrolled constitutive activation of the type I IFN system can lead to autoinflammation and autoimmunity, which is observed in autoimmune disorders such as systemic lupus erythematodes and in monogenic interferonopathies. They are caused by mutations in genes which are involved in sensing or metabolism of intracellular nucleic acids and DNA repair. Many authors described mechanisms of type I IFN secretion upon increased DNA damage, including the formation of micronuclei, cytosolic chromatin fragments and destabilization of DNA binding proteins. Hereditary cutaneous DNA damage syndromes, which are caused by mutations in proteins of the DNA repair, share laboratory and clinical features also seen in autoimmune disorders and interferonopathies; hence a potential role of DNA-damage-induced type I IFN secretion seems likely. Here, we aim to summarize possible mechanisms of IFN induction in cutaneous DNA damage syndromes with defects in the DNA double-strand repair and nucleotide excision repair. We review recent publications referring to Ataxia teleangiectasia, Bloom syndrome, Rothmund–Thomson syndrome, Werner syndrome, Huriez syndrome, and Xeroderma pigmentosum. Furthermore, we aim to discuss the role of type I IFN in cancer and these syndromes.

show abstract

“…The detailed mechanistic understanding of the primary events that trigger this activation is presently unclear. One possibility is that aberrantly localised cytosolic DNA, which arises from micronuclei and damaged mitochondria in A-T (10,12,13,15), can stimulate the non-canonical NF-κB pathway. However, mechanistic links between cytosolic DNA signalling and the non-canonical NF-κB pathway are yet to be defined (48).…”

Section: Discussionmentioning

confidence: 99%

Persistent DNA damage promotes microglial dysfunction in Ataxia-telangiectasia

Bourseguin

Cheng

Talbot

et al. 2021

Preprint

View full text Add to dashboard Cite

The autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterised by the progressive loss of cerebellar neurons. We find that DNA damage associated with ATM loss results in dysfunctional behaviour of human microglia, immune cells of the central nervous system. Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-κB transcriptional pathway and leads to excessive phagocytic clearance of neurites. Pathological phagocytosis of neuronal processes by microglia has also been observed in multiple sclerosis, Alzheimer′s and progranulin deficiency, suggesting a common mechanism that promotes neuronal damage. Activation of the RELB/p52 pathway in ATM-deficient microglia is driven by persistent DNA damage and is dependent on the NIK kinase. These results provide insights into the underlying mechanisms of aberrant microglial behaviour in Ataxia telangiectasia, potentially contributing to neurodegeneration.

show abstract

ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation

Cited by 148 publications

References 62 publications

Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA

Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA

Type I Interferon Induction in Cutaneous DNA Damage Syndromes

Persistent DNA damage promotes microglial dysfunction in Ataxia-telangiectasia

Contact Info

Product

Resources

About