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2024

Nat Commun. 2024 Jun 1;15(1):4696. doi: 10.1038/s41467-024-49066-7.

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

Samuel D Chauvin, Shoichiro Ando, Joe A Holley, Atsushi Sugie, Fang R Zhao, Subhajit Poddar, Rei Kato, Cathrine A Miner, Yohei Nitta, Siddharth R Krishnamurthy, Rie Saito, Yue Ning, Yuya Hatano, Sho Kitahara, Shin Koide, W Alexander Stinson, Jiayuan Fu, Nehalee Surve, Lindsay Kumble, Wei Qian, Oleksiy Polishchuk, Prabhakar S Andhey, Cindy Chiang, Guanqun Liu, Ludovic Colombeau, Raphaël Rodriguez, Nicolas Manel, Akiyoshi Kakita, Maxim N Artyomov, David C Schultz, P Toby Coates, Elisha D O Roberson, Yasmine Belkaid, Roger A Greenberg, Sara Cherry, Michaela U Gack, Tristan Hardy, Osamu Onodera, Taisuke Kato, Jonathan J Miner

Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University, Niigata, Japan. Department of Neuroscience of Disease, Brain Research Institute, Niigata University, Niigata, Japan. Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Department of Pathology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University, Niigata, Japan. Department of Pathology and Immunology, Washington University in Saint Louis, Saint Louis, MO, USA. Department of Microbiology, The University of Chicago, Chicago, IL, USA. Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL, USA. Equipe Labellisée Ligue Contre le Cancer, Institut Curie, CNRS, INSERM, PSL Research University, Paris, France. INSERM U932, Institut Curie, PSL Research University, Paris, France. High-throughput Screening Core, University of Pennsylvania, Philadelphia, PA, USA. Central and Northern Adelaide Renal and Transplantation Service (CNARTS), The Royal Adelaide Hospital, Adelaide, South Australia, Australia. School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia. Institut Pasteur, Paris, France. Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Genetics, Repromed, Monash IVF, Dulwich, South Australia, Australia. Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia. Department of Molecular Neuroscience, Brain Science Branch, Brain Research Institute, Niigata University, Niigata, Japan. Division of Rheumatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. RVCL Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Department of Medicine, Washington University in Saint Louis, Saint Louis, MO, USA. Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. J Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Penn Colton Center for Autoimmunity, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Service type: Knock-in mice

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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