PXD051905-1

PXD051905 is an original dataset announced via ProteomeXchange.

Title	Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans
Description	Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the liver, brain, kidney and retina. 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 the radiation injury, we reasoned that nuclear TREX1 promotes DNA damage. Here, we show that RVCL-associated TREX1 variants cause 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 new mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.
HostingRepository	PRIDE
AnnounceDate	2024-05-30
AnnouncementXML	Submission_2024-05-30_09:01:17.509.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD051905
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Michaela Gack
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2024-04-30 15:29:15	ID requested
⏵ 1	2024-05-30 09:01:17	announced
2	2024-10-22 06:43:21	announced	2024-10-22: Updated project metadata.

10.6019/PXD051905;

submitter keyword: BRCA1, retinal vasculopathy with cerebral leukoencephalopathy, cerebroretinal vasculopathy, RVCL-S, RVCL,TREX1, interferon, inflamm-aging, HERNS, CRV, dementia, DNA damage response, small vessel disease, vasculopathy

Jonathan Miner
contact affiliation	Division of Rheumatology, Departments of Medicine and Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
contact email	Jonathan.Miner@PennMedicine.UPenn.edu
lab head
Michaela Gack
contact affiliation	Cleveland Clinic
contact email	gackm@ccf.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD051905
     1. Label: PRIDE project
     2. Name: Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans