Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans
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Published:2024-06-01
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Chauvin Samuel D.ORCID, Ando Shoichiro, Holley Joe A., Sugie AtsushiORCID, Zhao Fang R.ORCID, Poddar Subhajit, Kato Rei, Miner Cathrine A., Nitta YoheiORCID, Krishnamurthy Siddharth R., Saito RieORCID, Ning Yue, Hatano Yuya, Kitahara Sho, Koide ShinORCID, Stinson W. Alexander, Fu Jiayuan, Surve Nehalee, Kumble Lindsay, Qian Wei, Polishchuk Oleksiy, Andhey Prabhakar S., Chiang Cindy, Liu GuanqunORCID, Colombeau Ludovic, Rodriguez RaphaëlORCID, Manel NicolasORCID, Kakita Akiyoshi, Artyomov Maxim N.ORCID, Schultz David C.ORCID, Coates P. Toby, Roberson Elisha D. O., Belkaid Yasmine, Greenberg Roger A.ORCID, Cherry SaraORCID, Gack Michaela U.ORCID, Hardy Tristan, Onodera OsamuORCID, Kato TaisukeORCID, Miner Jonathan J.ORCID
Abstract
AbstractAge-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.
Funder
U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke Rheumatology Research Foundation The Clayco Foundation Penn Colton Center for Autoimmunity Penn RVCL Sisters Fund U.S. Department of Health & Human Services | National Institutes of Health Japan Agency for Medical Research and Development MEXT | Japan Society for the Promotion of Science Osaka Medical Research Foundation for Intractable Diseases
Publisher
Springer Science and Business Media LLC
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