TY - JOUR
T1 - Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans
AU - Chauvin, Samuel D.
AU - Ando, Shoichiro
AU - Holley, Joe A.
AU - Sugie, Atsushi
AU - Zhao, Fang R.
AU - Poddar, Subhajit
AU - Kato, Rei
AU - Miner, Cathrine A.
AU - Nitta, Yohei
AU - Krishnamurthy, Siddharth R.
AU - Saito, Rie
AU - Ning, Yue
AU - Hatano, Yuya
AU - Kitahara, Sho
AU - Koide, Shin
AU - Stinson, W. Alexander
AU - Fu, Jiayuan
AU - Surve, Nehalee
AU - Kumble, Lindsay
AU - Qian, Wei
AU - Polishchuk, Oleksiy
AU - Andhey, Prabhakar S.
AU - Chiang, Cindy
AU - Liu, Guanqun
AU - Colombeau, Ludovic
AU - Rodriguez, Raphaël
AU - Manel, Nicolas
AU - Kakita, Akiyoshi
AU - Artyomov, Maxim N.
AU - Schultz, David C.
AU - Coates, P. Toby
AU - Roberson, Elisha D.O.
AU - Belkaid, Yasmine
AU - Greenberg, Roger A.
AU - Cherry, Sara
AU - Gack, Michaela U.
AU - Hardy, Tristan
AU - Onodera, Osamu
AU - Kato, Taisuke
AU - Miner, Jonathan J.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85195010024&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-49066-7
DO - 10.1038/s41467-024-49066-7
M3 - Article
C2 - 38824133
AN - SCOPUS:85195010024
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4696
ER -