TREX1 – Apex predator of cytosolic DNA metabolism

Simpson, Sean R.; Hemphill, Wayne O.; Hudson, Teesha; Perrino, Fred W.

doi:10.1016/j.dnarep.2020.102894

Cited by 34 publications

(33 citation statements)

References 112 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…WGS in the patient revealed the presence of a heterozygous pathogenic variant in the TREX1 gene, an enzyme preventing inflammation and autoimmunity by degrading cytosolic DNA [29]. The variant was a ten base-pair insertion causing a frameshift and a premature translation termination, confirming the diagnosis of HERNS syndrome.…”

Section: P12mentioning

confidence: 79%

Whole-Genome Sequencing in Diagnostics of Selected Slovenian Undiagnosed Patients with Rare Disorders

Bergant¹,

Maver²,

Peterlin³

2021

Life

View full text Add to dashboard Cite

Several patients with rare genetic disorders remain undiagnosed following comprehensive diagnostic testing using whole-exome sequencing (WES). In these patients, pathogenic genetic variants may reside in intronic or regulatory regions or they may emerge through mutational mechanisms not detected by WES. For this reason, we implemented whole-genome sequencing (WGS) in routine clinical diagnostics of patients with undiagnosed genetic disorders and report on the outcome in 30 patients. Criteria for consideration included (1) negative WES, (2) a high likelihood of a genetic cause for the disorders, (3) positive family history, (4) detection of large blocks of homozygosity or (5) detection of a single pathogenic variant in a gene associated with recessive conditions. We successfully discovered a causative genetic variant in 6 cases, a retrotranspositional event in the APC gene, non-coding variants in the intronic region of the OTC gene and the promotor region of the UFM1 gene, repeat expansion in the RFC1 gene and a single exon duplication in the CNGB3 gene. We also discovered one coding variant, an indel, which was missed by variant caller during WES data analysis. Our study demonstrates the impact of WGS in the group of patients with undiagnosed genetic diseases after WES in the clinical setting and the diversity of mutational mechanisms discovered, which would remain undetected using other methods.

show abstract

Section: P12mentioning

confidence: 79%

Whole-Genome Sequencing in Diagnostics of Selected Slovenian Undiagnosed Patients with Rare Disorders

Bergant¹,

Maver²,

Peterlin³

2021

Life

View full text Add to dashboard Cite

show abstract

“…DNA produced during the resolution of replication stress or retroelements such as retrotransposons are also a source of aberrant cytoplasmic DNA (Figure 6A). This DNA is usually degraded by the TREX1 protein, which is a DNA exonuclease that clears normal endogenous cytosolic DNA to prevent aberrant stimulation of the cGAS pathway [99]. Mechanistically, cGAS activation by cytosolic DNA leads to the generation of cyclic GMP-AMP (cGAMP), which binds to the receptor STImulator of INterferon Genes (STING).…”

Section: Cytoplasmic Dna Induces Inflammation By Cgas/sting Pathwaymentioning

confidence: 99%

Section: Cytoplasmic Dna Induces Inflammation By Cgas/sting Pathwaymentioning

confidence: 99%

“…Mechanistic studies have highlighted TREX1 as an important contributor of DNA breaks and chromothripsis [ 70 , 117 ]. TREX1 is a powerful DNA exonuclease that degrades both double- and single-strand DNA from the 3′-terminus and that is required for clearing cytosolic DNA to prevent aberrant inflammation and autoimmunity [ 99 ]. In addition, APOBEC3 is likely involved in the generation of the hyper mutated pattern kataegis observed in this model [ 117 ] ( Figure 8 ).…”

Section: Chromosomal Instability Associated To Nedmentioning

confidence: 99%

See 1 more Smart Citation

Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

Gauthier

Comaills

2021

IJMS

View full text Add to dashboard Cite

The dynamic nature of the nuclear envelope (NE) is often underestimated. The NE protects, regulates, and organizes the eukaryote genome and adapts to epigenetic changes and to its environment. The NE morphology is characterized by a wide range of diversity and abnormality such as invagination and blebbing, and it is a diagnostic factor for pathologies such as cancer. Recently, the micronuclei, a small nucleus that contains a full chromosome or a fragment thereof, has gained much attention. The NE of micronuclei is prone to collapse, leading to DNA release into the cytoplasm with consequences ranging from the activation of the cGAS/STING pathway, an innate immune response, to the creation of chromosomal instability. The discovery of those mechanisms has revolutionized the understanding of some inflammation-related diseases and the origin of complex chromosomal rearrangements, as observed during the initiation of tumorigenesis. Herein, we will highlight the complexity of the NE biology and discuss the clinical symptoms observed in NE-related diseases. The interplay between innate immunity, genomic instability, and nuclear envelope leakage could be a major focus in future years to explain a wide range of diseases and could lead to new classes of therapeutics.

show abstract

“…In Trex −/− mice, deletion of cGAS, STING, or IRF3, abrogates this chronic inflammatory state [ 17 , 51 , 52 ]. Thus, various forms of self-DNA are frequently released into cytoplasm that can activate the cGAS-STING signaling and IFNI production unless they are rigorously degraded [ 53 ].…”

Section: Cytosolic Dna Sensorsmentioning

confidence: 99%

Cytosolic Self-DNA—A Potential Source of Chronic Inflammation in Aging

Akbari

Shanley

Bohr

et al. 2021

Cells

View full text Add to dashboard Cite

Aging is the consequence of a lifelong accumulation of stochastic damage to tissues and cellular components. Advancing age closely associates with elevated markers of innate immunity and low-grade chronic inflammation, probably reflecting steady increasing incidents of cellular and tissue damage over the life course. The DNA sensing cGAS-STING signaling pathway is activated by misplaced cytosolic self-DNA, which then initiates the innate immune responses. Here, we hypothesize that the stochastic release of various forms of DNA from the nucleus and mitochondria, e.g., because of DNA damage, altered nucleus integrity, and mitochondrial damage, can result in chronic activation of inflammatory responses that characterize the aging process. This cytosolic self-DNA-innate immunity axis may perturb tissue homeostasis and function that characterizes human aging and age-associated pathology. Proper techniques and experimental models are available to investigate this axis to develop therapeutic interventions.

show abstract

TREX1 – Apex predator of cytosolic DNA metabolism

Cited by 34 publications

References 112 publications

Whole-Genome Sequencing in Diagnostics of Selected Slovenian Undiagnosed Patients with Rare Disorders

Whole-Genome Sequencing in Diagnostics of Selected Slovenian Undiagnosed Patients with Rare Disorders

Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

Cytosolic Self-DNA—A Potential Source of Chronic Inflammation in Aging

Contact Info

Product

Resources

About