Phenotype of ribonuclease 1 deficiency in mice

Garnett, Emily; Lomax, Jo E.; Mohammed, Bassem M.; Gailani, David; Sheehan, John P.; Raines, Ronald T.

doi:10.1261/rna.070433.119

Cited by 16 publications

(14 citation statements)

References 69 publications

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“…Additionally, prothrombotic eRNA was also associated to fibrin-rich thrombi in an arterial thrombosis mouse model and pretreatment of mice with RNase1 considerably reduced eRNA containing thrombi and delayed vessel occlusion (Kannemeier et al, 2007). These findings are in line with the phenotype of recently described RNase1 deficient mice that showed increased eRNA plasma levels and more rapid blood clotting, indicating a crucial role for RNase1 in regulation of blood coagulation (Garnett et al, 2019).…”

Section: Atherosclerosis and Thrombosissupporting

confidence: 78%

Endothelial Ribonuclease 1 in Cardiovascular and Systemic Inflammation

Bedenbender

Schmeck

2020

Front. Cell Dev. Biol.

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The vascular endothelial cell layer forms the inner lining of all blood vessels to maintain proper functioning of the vascular system. However, dysfunction of the endothelium depicts a major issue in context of vascular pathologies, such as atherosclerosis or thrombosis that cause several million deaths per year worldwide. In recent years, the endothelial extracellular endonuclease Ribonuclease 1 (RNase1) was described as a key player in regulation of vascular homeostasis by protecting endothelial cells from detrimental effects of the damage-associated molecular pattern extracellular RNA upon acute inflammation. Despite this protective function, massive dysregulation of RNase1 was observed during prolonged endothelial cell inflammation resulting in progression of several vascular diseases. For the first time, this review article outlines the current knowledge on endothelial RNase1 and its role in function and dysfunction of the endothelium, thereby focusing on the intensive research from recent years: Uncovering the underlying mechanisms of RNase1 function and regulation in response to acute as well as long-term inflammation, the role of RNase1 in context of vascular, inflammatory and infectious diseases and the potential to develop novel therapeutic options to treat these pathologies against the background of RNase1 function in endothelial cells.

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Section: Atherosclerosis and Thrombosissupporting

confidence: 78%

Endothelial Ribonuclease 1 in Cardiovascular and Systemic Inflammation

Bedenbender

Schmeck

2020

Front. Cell Dev. Biol.

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“…Clearly, biofluids are a much more complex environment than conditioned medium from cultured cells. However, considering that at least in plasma, RNase 1 constitutes the majority of ribonucleolytic activity ( 82 ), our results position RNase 1 as a likely candidate for producing extracellular tRNA halves and Y RNA fragments in vivo . Future studies will have to validate this, as well as address the functional and diagnostic relevance of these extracellular fragments.…”

Section: Discussionmentioning

confidence: 74%

“…While the catalytic mechanism of RNase 1 has been studied in detail, the role of this enzyme remains less well defined. Several studies have suggested RNase 1 as a scavenger of extracellular RNA, involved in immunomodulation and modulation of coagulation ( 82–84 ). The results of our study suggest a novel role for RNase 1 as a factor involved in production of abundant extracellular tRNA halves and distinct Y RNA fragments.…”

Section: Discussionmentioning

confidence: 99%

Processing by RNase 1 forms tRNA halves and distinct Y RNA fragments in the extracellular environment

Nechooshtan

Yunusov

Chang

et al. 2020

Nucleic Acids Research

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Abstract Extracellular RNAs participate in intercellular communication, and are being studied as promising minimally invasive diagnostic markers. Several studies in recent years showed that tRNA halves and distinct Y RNA fragments are abundant in the extracellular space, including in biofluids. While their regulatory and diagnostic potential has gained a substantial amount of attention, the biogenesis of these extracellular RNA fragments remains largely unexplored. Here, we demonstrate that these fragments are produced by RNase 1, a highly active secreted nuclease. We use RNA sequencing to investigate the effect of a null mutation of RNase 1 on the levels of tRNA halves and Y RNA fragments in the extracellular environment of cultured human cells. We complement and extend our RNA sequencing results with northern blots, showing that tRNAs and Y RNAs in the non-vesicular extracellular compartment are released from cells as full-length precursors and are subsequently cleaved to distinct fragments. In support of these results, formation of tRNA halves is recapitulated by recombinant human RNase 1 in our in vitro assay. These findings assign a novel function for RNase 1, and position it as a strong candidate for generation of tRNA halves and Y RNA fragments in biofluids.

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“…Although there is good evidence that cell-free DNA plays a crucial role in the crosstalk between tissue injury, inflammation, and coagulation, very little is known about the physiological and pathophysiological roles of eRNA in sepsis (27). It has been suggested that the negative charge of eRNA builds the structural feature rendering eRNA capable of activating factor XII and, hence, coagulation (28,29). Moreover, Chen and colleagues report that eRNA contributes to myocardial inflammation via TLR-3-Trif signaling (23).…”

Section: Discussionmentioning

confidence: 99%