Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response

Du, Hekang; Xiao, Nanyang; Zhang, Sitong; Zhou, Xueyuan; Zhang, Yangfan; Lu, Zengzeng; Fu, Yuchuan; Huang, Mengli; Xu, San; Chen, Qi

doi:10.1016/j.isci.2023.107090

Cited by 9 publications

(9 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nuclear DNA damage leads to DNA leakage into the cytosol, kickstarting cGAS-STING (45). TREX1 mitigates DNA damage, in part, by degrading cytosolic DNA and preventing cGAS-STING and downstream interferon gene cascades (12,46). Here we demonstrate that a small synthetic ncRNA molecule, TY1, upregulates TREX1 and minimizes lethal cardiac injury post-MI.…”

Section: Discussionmentioning

confidence: 66%

“…The proinflammatory impact of DNA damage is particularly evident in macrophages, which orchestrate acute and chronic inflammatory responses (7,8). TREX1 is induced in macrophages in response to proinflammatory stimuli; indeed, TREX1 deficiency induces an exaggerated proinflammatory response in macrophages (9), systemic autoimmunity (10,11) and accelerated senescence (12). Nevertheless, the converse conjecture remains unexplored: might TREX1 augmentation be helpful in disorders of inflammation?…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury

Ibrahim,

Ciullo,

Miyamoto

et al. 2024

Preprint

View full text Add to dashboard Cite

Noncoding RNAs (ncRNAs) are increasingly recognized as bioactive. Here we report the development of TY1, a synthetic ncRNA bioinspired by a naturally-occurring human small Y RNA with immunomodulatory properties. TY1 upregulates TREX1, an exonuclease that rapidly degrades cytosolic DNA. In preclinical models of myocardial infarction (MI) induced by ischemia/reperfusion, TY1 reduced scar size. The cardioprotective effect of TY1 was abrogated by prior depletion of macrophages and mimicked by adoptive transfer of macrophages exposed either to TY1 or TREX1. Inhibition of TREX1 in macrophages blocked TY1 cardioprotection. Consistent with a central role for TREX1, TY1 attenuated DNA damage in the post-MI heart. This novel mechanism—pharmacologic upregulation of TREX1 in macrophages—establishes TY1 as the prototype for a new class of ncRNA drugs with disease-modifying bioactivity.One Sentence SummaryUpregulation of three prime exonuclease, TREX1, in macrophages enhances tissue repair post myocardial infarction.

show abstract

Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury

Ibrahim,

Ciullo,

Miyamoto

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…The efficacy and potency of TREX1 inhibitors in preventing TREX1-mediated pathology in animals is under investigation and will be considered with caution. Indeed, genetic deletion of TREX1 also causes DNA damage via inflammatory pathways 71 , suggesting that small molecular inhibition of the TREX1 enzyme may also carry risks of causing genomic instability via indirect mechanisms. In addition, caution is advised when exposing RVCL patients to genotoxic agents and radiation, as treatments that elevate TREX1 expression or induce DNA damage may exacerbate disease progression or trigger excessive inflammation.…”

Section: Discussionmentioning

confidence: 99%

Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans

Chauvin,

Ando,

Holley

et al. 2024

Nat Commun

View full text Add to dashboard Cite

Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3′−5′ DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of radiation injury, we reasoned that nuclear TREX1 would cause DNA damage. Here, we show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.

show abstract

“…PARP inhibitors (PARPi) enhance cancer cell immunogenicity via the cGAS-STING signaling pathway in the context of ERCC1 or the breast cancer susceptibility genes (BRCA) defects. Several studies have indicated that changes in chromatin states induced by chemoradiotherapy significantly influence cGAS recruitment, whereas the inner nuclear membrane-anchored exonuclease three prime repair exonuclease 1 (TREX1) degrades DNA and mitigates the effects of IFN-α/β 36 , 37 . Recently, our group has shown that multiple cancer cells induce chromatin untethering and activity inhibition of cGAS through competitive uptake of methionine.…”

Section: The Cgas-sting Pathway In Cancer Biologymentioning

confidence: 99%

Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies

Zhang,

Yu,

Peng

et al. 2024

Cancer Biol Med

View full text Add to dashboard Cite

The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment. Within this landscape, the innate immune system, a critical sentinel protecting against tumor incursion, is a key player. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway has been found to be a linchpin of innate immunity: activation of this signaling pathway orchestrates the production of type I interferon (IFN-α/β), thus fostering the maturation, differentiation, and mobilization of immune effectors in the tumor microenvironment. Furthermore, STING activation facilitates the release and presentation of tumor antigens, and therefore is an attractive target for cancer immunotherapy. Current strategies to activate the STING pathway, including use of pharmacological agonists, have made substantial advancements, particularly when combined with immune checkpoint inhibitors. These approaches have shown promise in preclinical and clinical settings, by enhancing patient survival rates. This review describes the evolving understanding of the cGAS-STING pathway’s involvement in tumor biology and therapy. Moreover, this review explores classical and non-classical STING agonists, providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies. Despite challenges and complexities, the cGAS-STING pathway, a promising avenue for enhancing cancer treatment efficacy, has the potential to revolutionize patient outcomes.

show abstract

Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response

Cited by 9 publications

References 64 publications

Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury

Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury

Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans

Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies

Contact Info

Product

Resources

About