The evidence for a microRNA product of human DROSHA gene

Mechtler, Peter; Johnson, Sydney; Slabodkin, Hannah; Cohanim, Amir B.; Brodsky, Leonid; Kandel, Eugene

doi:10.1080/15476286.2017.1342934

Cited by 9 publications

(9 citation statements)

References 38 publications

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“…Splicing regulation by DROSHA was recently corroborated by the discovery of a pri-miRNA-like hairpin located across a specific exon-intron junction of the human DROSHA gene itself ( Fig. 2E) [59,77,78]. The DROSHA hairpin, likely derived from transposable elements, is structurally conserved among placental mammals but seems to be functionally divergent.…”

Section: Regulation Of Transcription and Rna Processingmentioning

confidence: 83%

Emerging roles of DROSHA beyond primary microRNA processing

Lee

Shin

2017

RNA Biology

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DROSHA is the catalytic subunit of the Microprocessor complex, which initiates microRNA (miRNA) maturation in the nucleus by recognizing and cleaving hairpin precursors embedded in primary transcripts. However, accumulating evidence suggests that not all hairpin substrates of DROSHA are associated with the generation of functional small RNAs. By targeting those hairpins, DROSHA regulates diverse aspects of RNA metabolism across the transcriptome, serves as a line of defense against the expression of potentially deleterious elements, and permits cell fate determination and differentiation. DROSHA is also versatile in the way that it executes these noncanonical functions, occasionally depending on its RNA-binding activity rather than its catalytic activity. Herein, we discuss the functional and mechanistic diversity of DROSHA beyond the miRNA biogenesis pathway in light of recent findings.

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Section: Regulation Of Transcription and Rna Processingmentioning

confidence: 83%

Emerging roles of DROSHA beyond primary microRNA processing

Lee

Shin

2017

RNA Biology

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“…Lastly, one puzzling aspect is the lack of clustering of DROSHA -mutant tumors with DGCR8 -mutant tumors by miRNA expression analysis. Possible explanations lie within the recent appreciation that the functions of the DROSHA protein extend beyond miRNA processing, and include the recognition and cleavage of mRNAs and potentially ribosomal RNAs, as well as modification of its own expression [ 26 - 28 ].…”

Section: Resultsmentioning

confidence: 99%

A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor

et al. 2017

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Genome-wide sequencing, mRNA and miRNA expression, DNA copy number and methylation analyses were performed on 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, FAM123B, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), mutations were identified in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and let-7a loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.

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“…As a nuclear RNase III enzyme, Drosha controls the initial step of miRNA biogenesis ( Aguado et al, 2017 ; Mechtler et al, 2017 ). miRNAs have the ability to orchestrate the maintenance of adult neural cell traits, promote cellular homeostasis, and dampen endogenous and exogenous stress responses ( Yokota, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, LRRK2 can activate MAPK signaling cascades, such as the p38 MAPK pathway, by phosphorylating MAPK kinases (MKKs) ( Gloeckner et al, 2009 ; Hsu et al, 2010a ). Under stress conditions, activated p38 inhibits the cellular survival program that is mediated by Drosha, which is a functional nuclease that processes long primary microRNAs (pri-miRNAs) into precursor microRNAs (pre-miRNAs) with its cofactor in the nucleus ( Hong et al, 2013 ; Yang et al, 2015 ; Mechtler et al, 2017 ). After TBI, phosphorylated p38 (p-p38) is significantly increased in the brain and participates in the pathological processes of TBI ( Tang et al, 2012 ; Yang et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

LRRK2 Contributes to Secondary Brain Injury Through a p38/Drosha Signaling Pathway After Traumatic Brain Injury in Rats

Qin

Gao

et al. 2018

Front. Cell. Neurosci.

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Leucine-rich repeat kinase 2 (LRRK2) is widely expressed in the brain and exerts neurotoxicity in Parkinson’s disease. The p38/Drosha signaling activation has been reported to increase cell death under stress. This study was designed to investigate the potential role and mechanism of LRRK2 in secondary brain injury after traumatic brain injury (TBI). A total of 130 male Sprague-Dawley rats were examined using a weight-drop model of TBI. The rats received the specific LRRK2 inhibitor PF-06447475 or LRRK2 pDNA alone or in combination with Drosha pDNA. Real-time PCR, western blot, immunofluorescence, neuronal apoptosis, brain water content, and neurological score analyses were conducted. Our results showed that after TBI, endogenous LRRK2 expression and p38 phosphorylation were increased, whereas Drosha expression was inhibited. Administration of the LRRK2 inhibitor PF-06447475 significantly reduced neuronal apoptosis, brain water content, and blood–brain barrier permeability 12 h after TBI and ameliorated neurological deficits 72 h after TBI, which was concomitant with decreased p38 phosphorylation and increased Drosha expression. Conversely, LRRK2 overexpression induced the opposite effect. Moreover, the neurotoxic effects of LRRK2 on TBI were also eliminated by Drosha overexpression. Altogether, these findings demonstrate the importance of TBI-induced LRRK2 upregulation during the induction of post-traumatic neurological injury, which may be partially mediated through a p38/Drosha signaling pathway.

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The evidence for a microRNA product of human DROSHA gene

Cited by 9 publications

References 38 publications

Emerging roles of DROSHA beyond primary microRNA processing

Emerging roles of DROSHA beyond primary microRNA processing

A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor

LRRK2 Contributes to Secondary Brain Injury Through a p38/Drosha Signaling Pathway After Traumatic Brain Injury in Rats

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