The cGAS/STING/TBK1/IRF3 innate immunity pathway maintains chromosomal stability through regulation of p21 levels

Basit, Abdul; Cho, Min-Guk; Kim, Eui Yun; Kwon, Duck-Hee; Kang, Sang-Won; Lee, Jae Ho

doi:10.1038/s12276-020-0416-y

Cited by 74 publications

(51 citation statements)

References 35 publications

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“…This shows that, unexpectedly, the mechanism underlying the induction of cell senescence by strong and prolonged confinement is specifically due to TREX1-dependent DNA damage in cells with NE ruptures. Importantly, the senescence phenotype did not require the activation of the canonical cGAS pathway ( 31 ), since RPE1 cells do not express cGAS ( Fig S3H, 32 ). Together, these results show that TREX1-dependent chronic DNA damage induced upon strong confinement triggers hallmarks of senescence in normal RPE1 and MCF10A cells, but not in transformed DCIS cells.…”

Section: Resultsmentioning

confidence: 99%

Compromised nuclear envelope integrity drives tumor cell invasion

Nader

Agüera-González

Routet

et al. 2020

Preprint

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While mutations leading to a fragile envelope of the cell nucleus are well known to cause diseases such as muscular dystrophies or accelerated aging, the pathophysiological consequences of the recently discovered mechanically induced nuclear envelope ruptures in cells harboring no mutation are less known. Here we show that repeated loss of nuclear envelope integrity in nuclei experiencing mechanical constraints promotes senescence in nontransformed cells, and induces an invasive phenotype including increased collagen degradation in human breast cancer cells, both in vitro and in a mouse xenograft model of breast cancer progression. We show that these phenotypic changes are due to the presence of chronic DNA damage and activation of the ATM kinase. In addition, we found that depletion of the cytoplasmic exonuclease TREX1 is sufficient to abolish the DNA damage in mechanically challenged nuclei and to suppress the phenotypes associated with the loss of nuclear envelope integrity. Our results also show that TREX1-dependent DNA damage induced by physical confinement of tumor cells inside the mammary duct drives the progression of in situ breast carcinoma to the invasive stage. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells. Main text:( 16,21-23 ), and corresponds to cells squeezing each other as they move. These deformed nuclei were also more often positive for γH2AX than less deformed ones, and in general displayed more intense γH2AX staining than nuclei in the bulk of the tumor ( Fig. 1A-C). This suggests that, at the in situ stage of human breast carcinoma, strands of motile cells at the periphery of the tumor exhibit pronounced nuclear deformation, associated with elevated DNA damage.We then investigated a xenograft mouse model based on the intraductal (intra-nipple) injection of transformed human breast MCF10DCIS.com (DCIS) cells, which are derived from the nontransformed MCF10A cell line, and that recapitulates the transition from in situ to invasive stages of breast cancer progression ( 17,24 ). Tumors at various stages were analyzed. In situ tumors (further divided in early and advanced stages based on the continuity of the myoepithelial layer) are characterized by a myoepithelial layer (stained with smooth muscle actin) surrounding human xenograft cells that were identified by the human-specific KU70 antibody. In order to verify whether human tumor cells similarly experience DNA damage in the tumor xenografts, tumor sections were stained with γH2AX ( Fig. 1E-F, Fig. S1A). Similar to human tumor specimens, xenograft tumors displayed numerous deformed nuclei, mostly found at the periphery of the tumor mass, close to the myoepithelium, especially in ducts inflated with large tumors (Fig. 1E-F), and enriched in regions showing micro-invasive foci. Strikingly, these regions were also enriched in γH2AX-positive nuclei (Fig. 1F). Since γH2AX is also known...

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Section: Resultsmentioning

confidence: 99%

Compromised nuclear envelope integrity drives tumor cell invasion

Nader

Agüera-González

Routet

et al. 2020

Preprint

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“…The formation of micronuclei appears to be cell cycle dependent as it is greatly augmented by passage through the mitotic phase of the cell cycle, which results in the formation of chromatin bridges and mis-segregated chromosomes [1,5,52,53]. cGAS knockdown in combination with mitotic arrest increased micronuclei formation and chromosomal segregation defects, whereas inhibition of the mitotic inducer cyclin dependent kinase 1 (CDK1) or overexpression of the cell cycle inhibitor p21, which inhibits the transition of cells from G2 into the mitotic phase, reduced micronuclei formation [53,54]. Furthermore, despite hosting damaged DNA, cells that exit mitotic cell cycle into G0 stage showed impaired micronuclei formation, lending further support to micronuclei as the products of mitosis [50] cGAS can be localized to the foci of nuclear envelope disruption [49], and the rupture of the micronuclei spills genomic DNA into the cytosol, resulting in cGAS-STING activation [55,56].…”

Section: Micronuclei Formation and Breakdownmentioning

confidence: 99%

cGAS-STING pathway in oncogenesis and cancer therapeutics

et al. 2020

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The host innate immunity offers the first line of defense against infection. However, recent evidence shows that the host innate immunity is also critical in sensing the presence of cytoplasmic DNA derived from genomic instability events, such as DNA damage and defective cell cycle progression. This is achieved through the cyclic GMP-AMP synthase (cGAS)/Stimulator of interferon (IFN) genes (STING) pathway. Here we discuss recent insights into the regulation of this pathway in cancer immunosurveillance, and the downstream signaling cascades that coordinate immune cell recruitment to the tumor microenvironment to destroy transformed cells through cellular senescence or cell death programs. Its central role in immunosurveillance positions the cGAS-STING pathway as an attractive anti-cancer immunotherapeutic drug target for chemical agonists or vaccine adjuvants and suggests a key node to be targeted in a synthetic lethal approach. We also discuss adaptive mechanisms used by cancer cells to circumvent cGAS-STING signaling and present evidence linking chronic cGAS-STING activation to inflammation-induced carcinogenesis, cautioning against the use of activating the cGAS-STING pathway as an anti-tumor immunotherapy. A deeper mechanistic understanding of the cGAS-STING pathway will aid in the identification of potentially efficacious anti-cancer therapeutic targets. www.oncotarget.com Jackson for editing and providing comments on the manuscript.

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“…Interestingly, haploinsufficiency in the STING activating kinase TANK-binding kinase (TBK1) [ 135 ] is associated with fALS and FTD [ 136 , 137 ] ( Figure 5 B). Within this pathway, TBK1 is important for several functions, including maintenance of chromosomal stability [ 138 ]. A functional cGAS/STING pathway is also known to be required for normal chromosomal segregation in cancer cells via a p21-dependent mechanism modulating G2/M transition [ 138 ].…”

Section: Neuroinflammation and Ddr In Alsmentioning

confidence: 99%

“…Within this pathway, TBK1 is important for several functions, including maintenance of chromosomal stability [ 138 ]. A functional cGAS/STING pathway is also known to be required for normal chromosomal segregation in cancer cells via a p21-dependent mechanism modulating G2/M transition [ 138 ]. The putative genome surveillance role in post-mitotic non-replicating cells is less clear.…”

Section: Neuroinflammation and Ddr In Alsmentioning

confidence: 99%

The role of DNA damage response in amyotrophic lateral sclerosis

Sun

Curle

Haider

et al. 2020

Essays in Biochemistry

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Amyotrophic lateral sclerosis (ALS) is a rapidly disabling and fatal neurodegenerative disease. Due to insufficient disease-modifying treatments, there is an unmet and urgent need for elucidating disease mechanisms that occur early and represent common triggers in both familial and sporadic ALS. Emerging evidence suggests that impaired DNA damage response contributes to age-related somatic accumulation of genomic instability and can trigger or accelerate ALS pathological manifestations. In this review, we summarize and discuss recent studies indicating a direct link between DNA damage response and ALS. Further mechanistic understanding of the role genomic instability is playing in ALS disease pathophysiology will be critical for discovering new therapeutic avenues.

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The cGAS/STING/TBK1/IRF3 innate immunity pathway maintains chromosomal stability through regulation of p21 levels

Cited by 74 publications

References 35 publications

Compromised nuclear envelope integrity drives tumor cell invasion

Compromised nuclear envelope integrity drives tumor cell invasion

cGAS-STING pathway in oncogenesis and cancer therapeutics

The role of DNA damage response in amyotrophic lateral sclerosis

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