Human DNA Exonuclease TREX1 Is Also an Exoribonuclease That Acts on Single-stranded RNA

Yuan, Fenghua; Dutta, Tanmay; Song, Lei; Gu, Liya; Qian, Liangyue; Benitez, Anaid; Ning, Shunbin; Malhotra, Arun; Deutscher, Murray P.; Zhang, Yanbin

doi:10.1074/jbc.m115.653915

Cited by 40 publications

(28 citation statements)

References 33 publications

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“…For example, TREX1 has been shown to interact with PARP and facilitates its nuclear localization and activity35. In addition to ssDNA, TREX1 has now been implicated in the degradation of dsDNA and ssRNA3637. In fact, TREX1 has even been shown to have nuclease independent activities in the regulation of oligosaccharyltransferase that contributes to its role in immune regulation23.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

et al. 2016

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Rather than targeting tumour cells directly, elements of the tumour microenvironment can be modulated to sensitize tumours to the effects of therapy. Here we report a unique mechanism by which ectopic microRNA-103 can manipulate tumour-associated endothelial cells to enhance tumour cell death. Using gain-and-loss of function approaches, we show that miR-103 exacerbates DNA damage and inhibits angiogenesis in vitro and in vivo. Local, systemic or vascular-targeted delivery of miR-103 in tumour-bearing mice decreased angiogenesis and tumour growth. Mechanistically, miR-103 regulation of its target gene TREX1 in endothelial cells governs the secretion of pro-inflammatory cytokines into the tumour microenvironment. Our data suggest that this inflammatory milieu may potentiate tumour cell death by supporting immune activation and inducing tumour expression of Fas and TRAIL receptors. Our findings reveal miR-mediated crosstalk between vasculature and tumour cells that can be exploited to improve the efficacy of chemotherapy and radiation.

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Section: Discussionmentioning

confidence: 99%

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

et al. 2016

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“…Yang et al verified this hypothesis and provided evidence for accumulation of ssDNA in Trex1 null mouse fibroblasts . Subsequent studies showed that TREX1 is not only a DNA exonuclease, but also functions as an exoribonuclease, indicating that mutations in TREX1 can also lead to accumulation of RNA along with DNA .…”

Section: Genetic and Molecular Mechanisms Underlying Agsmentioning

confidence: 94%

Astrocytes, an active player in Aicardi–Goutières syndrome

et al. 2018

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Aicardi-Goutières syndrome (AGS) is an early-onset, autoimmune and genetically heterogeneous disorder with severe neurologic injury. Molecular studies have established that autosomal recessive mutations in one of the following genes are causative: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1/MDA5. The phenotypic presentation and pathophysiology of AGS is associated with over-production of the cytokine Interferon-alpha (IFN-α) and its downstream signaling, characterized as type I interferonopathy. Astrocytes are one of the major source of IFN in the central nervous system (CNS) and it is proposed that they could be key players in AGS pathology. Astrocytes are the most ubiquitous glial cell in the CNS and perform a number of crucial and complex functions ranging from formation of blood-brain barrier, maintaining ionic homeostasis, metabolic support to synapse formation and elimination in healthy CNS. Involvement of astrocytic dysfunction in neurological diseases-Alexander's disease, Epilepsy, Alzheimer's and amyotrophic lateral sclerosis (ALS)-has been well-established. It is now known that compromised astrocytic function can contribute to CNS abnormalities and severe neurodegeneration, nevertheless, its contribution in AGS is unclear. The current review discusses known molecular and cellular pathways for AGS mutations and how it stimulates IFN-α signaling. We shed light on how astrocytes might be key players in the phenotypic presentations of AGS and emphasize the cell-autonomous and non-cell-autonomous role of astrocytes. Understanding the contribution of astrocytes will help reveal mechanisms underlying interferonopathy and develop targeted astrocyte specific therapeutic treatments in AGS.

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“…Additionally, it has been implicated in the regulation of BER through enhancing PARP1 [poly(ADP‐ribose) polymerase 1] activity. Moreover, TREX1 also possesses exoribonuclease activity and plays a role in the degradation of damaged tRNA substrates . Indeed, a large cohort of BER proteins have been implicated in RNA metabolism, and will be further discussed.…”

Section: Links Between the Ddr And Rna Metabolism Pathwaysmentioning

confidence: 97%

“…Moreover, TREX1 also possesses exoribonuclease activity and plays a role in the degradation of damaged tRNA substrates. 57, 58 Indeed, a large cohort of BER proteins have been implicated in RNA metabolism, and will be further discussed. Interestingly, very few DNA double-strand break (DSB) repair proteins have been reported to possess a dual role in post-transcriptional RNA metabolism, with the exception of RNF8 (ring finger protein 8) and BRCA1 (breast and ovarian cancer susceptibility gene 1).…”

Section: Links Between the Ddr And Rna Metabolism Pathwaysmentioning

confidence: 99%

Dual roles of DNA repair enzymes in RNA biology/post‐transcriptional control

2016

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Despite consistent research into the molecular principles of the DNA damage repair pathway for almost two decades, it has only recently been found that RNA metabolism is very tightly related to this pathway, and the two ancient biochemical mechanisms act in alliance to maintain cellular genomic integrity. The close links between these pathways are well exemplified by examining the base excision repair pathway, which is now well known for dual roles of many of its members in DNA repair and RNA surveillance, including APE1, SMUG1, and PARP1. With additional links between these pathways steadily emerging, this review aims to provide a summary of the emerging roles for DNA repair proteins in the post-transcriptional regulation of RNAs. WIREs RNA 2016, 7:604-619. doi: 10.1002/wrna.1353 For further resources related to this article, please visit the WIREs website.

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Human DNA Exonuclease TREX1 Is Also an Exoribonuclease That Acts on Single-stranded RNA

Cited by 40 publications

References 33 publications

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

Astrocytes, an active player in Aicardi–Goutières syndrome

Dual roles of DNA repair enzymes in RNA biology/post‐transcriptional control

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