ArticleNature communications2024
Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Biomarker advancements in cerebral small vessel disease: An overview.Neural regeneration research · 2026Article
- Autoinflammatory syndromes of STING and TREX1 dysfunction.The Journal of clinical investigation · 2026Review
- First case ofFrontiers in immunology · 2026Article
- Article
- High-efficiency homology-directed insertion into the genome using the engineered homing endonuclease ARCUS.Nucleic acids research · 2025Article
- Misdirected yet intact TREX1 exonuclease activity causes human cerebral and systemic small vessel disease.Brain : a journal of neurology · 2025Article
- Association of DNA damage response pathway genes with rheumatoid arthritis risks: a case-control study.Scientific reports · 2025Article
- The pathogenesis of cerebral small vessel disease and vascular cognitive impairment.Physiological reviews · 2025Review
- Prevalence and impact of molecular variation in the three-prime repair exonuclease 1 TREX1 and its implications for oncology.Human genomics · 2025Article
- AP-1-dependent c-Fos activation by TREX1 drives M2 macrophage polarization and mitigates osteoarthritis progression.Cellular and molecular life sciences : CMLS · 2025Article
- The DNase TREX1 is a substrate of the intramembrane protease SPP with implications for disease pathogenesis.Cellular and molecular life sciences : CMLS · 2025Article
- Effect of methyl DNA adducts on 3'-5' exonuclease activity of human TREX1.The Biochemical journal · 2025Article
- The intersection of TREX1, cGAS, STING and the DNA damage theory of aging.Frontiers in aging · 2025Review
- Exploring targeted therapy in retinal vasculopathy with cerebral leukoencephalopathy: a case report and review of literature.Frontiers in immunology · 2025Review
- Prime Editor Gene Therapy and TREX1 Mosaicism in Retinal Vasculopathy with Cerebral Leukoencephalopathy.Journal of clinical immunology · 2024Article
- Review
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40 authors.
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Abstract
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.
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