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

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

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 () and Jonathan J. Miner ()
Additional contact information
Samuel D. Chauvin: University of Pennsylvania Perelman School of Medicine
Shoichiro Ando: Niigata University
Joe A. Holley: University of Pennsylvania Perelman School of Medicine
Atsushi Sugie: Niigata University
Fang R. Zhao: Washington University in Saint Louis
Subhajit Poddar: University of Pennsylvania Perelman School of Medicine
Rei Kato: Niigata University
Cathrine A. Miner: University of Pennsylvania Perelman School of Medicine
Yohei Nitta: Niigata University
Siddharth R. Krishnamurthy: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Rie Saito: Niigata University
Yue Ning: University of Pennsylvania Perelman School of Medicine
Yuya Hatano: Niigata University
Sho Kitahara: Niigata University
Shin Koide: Niigata University
W. Alexander Stinson: Washington University in Saint Louis
Jiayuan Fu: University of Pennsylvania Perelman School of Medicine
Nehalee Surve: University of Pennsylvania Perelman School of Medicine
Lindsay Kumble: University of Pennsylvania Perelman School of Medicine
Wei Qian: Washington University in Saint Louis
Oleksiy Polishchuk: University of Pennsylvania Perelman School of Medicine
Prabhakar S. Andhey: Washington University in Saint Louis
Cindy Chiang: The University of Chicago
Guanqun Liu: The University of Chicago
Ludovic Colombeau: PSL Research University
Raphaël Rodriguez: PSL Research University
Nicolas Manel: PSL Research University
Akiyoshi Kakita: Niigata University
Maxim N. Artyomov: Washington University in Saint Louis
David C. Schultz: University of Pennsylvania
P. Toby Coates: The Royal Adelaide Hospital
Elisha D. O. Roberson: Washington University in Saint Louis
Yasmine Belkaid: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Roger A. Greenberg: University of Pennsylvania
Sara Cherry: University of Pennsylvania Perelman School of Medicine
Michaela U. Gack: The University of Chicago
Tristan Hardy: Monash IVF
Osamu Onodera: Niigata University
Taisuke Kato: Niigata University
Jonathan J. Miner: University of Pennsylvania Perelman School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49066-7

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