Редактирование: DGCR8

Microprocessor complex subunit DGCR8 (DiGeorge syndrome critical region 8) [C22orf12] [DGCRK6] [LP4941]

==Publications==

{{medline-entry
|title=Epigenetic regulation of miR-29a/miR-30c/[[DNMT3A]] axis controls [[SOD2]] and mitochondrial oxidative stress in human mesenchymal stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32961441
|abstract=The use of human mesenchymal stem cells (hMSCs) in clinical applications requires large-scale cell expansion prior to administration. However, the prolonged culture of hMSCs results in cellular senescence, impairing their proliferation and therapeutic potentials. To understand the role of microRNAs (miRNAs) in regulating cellular senescence in hMSCs, we globally depleted miRNAs by silencing the DiGeorge syndrome critical region 8 ([[DGCR8]]) gene, an essential component of miRNA biogenesis. [[DGCR8]] knockdown hMSCs exhibited severe proliferation defects and senescence-associated alterations, including increased levels of reactive oxygen species (ROS). Transcriptomic analysis revealed that the antioxidant gene superoxide dismutase 2 ([[SOD2]]) was significantly downregulated in [[DGCR8]] knockdown hMSCs. Moreover, we found that [[DGCR8]] silencing in hMSCs resulted in hypermethylation in CpG islands upstream of [[SOD2]]. 5-aza-2'-deoxycytidine treatment restored [[SOD2]] expression and ROS levels. We also found that these effects were dependent on the epigenetic regulator DNA methyltransferase 3 alpha ([[DNMT3A]]). Using computational and experimental approaches, we demonstrated that [[DNMT3A]] expression was regulated by miR-29a-3p and miR-30c-5p. Overexpression of miR-29a-3p and/or miR-30c-5p reduced ROS levels in [[DGCR8]] knockdown hMSCs and rescued proliferation defects, mitochondrial dysfunction, and premature senescence. Our findings provide novel insights into hMSCs senescence regulation by the miR-29a-3p/miR-30c-5p/[[DNMT3A]]/[[SOD2]] axis.

|keywords=* Cellular senescence
* DNMT3A
* Human mesenchymal stem cells
* Mitochondrial oxidative stress
* SOD2
* microRNAs
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509080
}}
{{medline-entry
|title=HPV shapes tumor transcriptome by globally modifying the pool of RNA binding protein-binding motif.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31039132
|abstract=Human papillomavirus (HPV) positive head and neck cancer displayed specific transcription landscape but the underlying molecular mechanisms are not fully determined. Here, we interestingly found that HPV infection could globally elongate the 3'-untranslated regions (3'UTRs) in the majority of alternative polyadenylation (APA)-containing genes. Counterintuitively, the 3'UTR elongation does not affect their resident gene expression. Rather, they significantly increase the number of binding sites for RNA-binding proteins (RBPs) and subsequently upregulate a group of oncogenic genes by absorbing RBPs. A significant fraction of HPV affected genes are regulated through such mechanism that is 3'UTR-mediated recruitment of RBPs. As an example, we observed that HPV infection increases the length of 3'UTR of [[RBM25]] transcript and hence recruits much more RNA binding protein including [[FUS]] and [[DGCR8]]. Consequently, in the absence of [[FUS]] and [[DGCR8]] regulation, PD-1 was rescued and up-regulated after HPV infection. Taken together, our findings not only suggest a novel paradigm of how oncogenic viruses shape tumor transcriptome by modifying the 3'UTR, but also present a previously unrecognized layer of APA-RBP interplay in this molecular hierarchy. Modification of the pool of RBP-binding motif might expand our understandings into virus-associated carcinogenesis.
|mesh-terms=* 3' Untranslated Regions
* Databases, Genetic
* Head and Neck Neoplasms
* Humans
* MicroRNAs
* Papillomaviridae
* Papillomavirus Infections
* Squamous Cell Carcinoma of Head and Neck
* Transcriptome
* Up-Regulation
|keywords=* PD-1
* RBM25
* RNA-binding protein
* age-related disease
* aging
* alternative polyadenylation
* oncogenic viruses
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520004
}}
{{medline-entry
|title=miRNAs 182 and 183 are necessary to maintain adult cone photoreceptor outer segments and visual function.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25002228
|abstract=The outer segments of cones serve as light detectors for daylight color vision, and their dysfunction leads to human blindness conditions. We show that the cone-specific disruption of [[DGCR8]] in adult mice led to the loss of miRNAs and the loss of outer segments, resulting in photoreceptors with significantly reduced light responses. However, the number of cones remained unchanged. The loss of the outer segments occurred gradually over 1 month, and during this time the genetic signature of cones decreased. Reexpression of the sensory-cell-specific miR-182 and miR-183 prevented outer segment loss. These miRNAs were also necessary and sufficient for the formation of inner segments, connecting cilia and short outer segments, as well as light responses in stem-cell-derived retinal cultures. Our results show that miR-182- and miR-183-regulated pathways are necessary for cone outer segment maintenance in vivo and functional outer segment formation in vitro.
|mesh-terms=* Aging
* Animals
* Gene Knockout Techniques
* Humans
* Light
* Mice
* Mice, Transgenic
* MicroRNAs
* Retina
* Retinal Cone Photoreceptor Cells
* Retinal Rod Photoreceptor Cells
* Vision, Ocular

|full-text-url=https://sci-hub.do/10.1016/j.neuron.2014.06.020
}}
{{medline-entry
|title=[[DGCR8]]-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23773483
|abstract=The regulation of gene expression by microRNAs (miRNAs) is critical for normal development and physiology. Conversely, miRNA function is frequently impaired in cancer, and other pathologies, either by aberrant expression of individual miRNAs or dysregulation of miRNA synthesis. Here, we have investigated the impact of global disruption of miRNA biogenesis in primary fibroblasts of human or murine origin, through the knockdown of [[DGCR8]], an essential mediator of the synthesis of canonical miRNAs. We find that the inactivation of [[DGCR8]] in these cells results in a dramatic antiproliferative response, with the acquisition of a senescent phenotype. Senescence triggered by [[DGCR8]] loss is accompanied by the upregulation of the cell-cycle inhibitor p21CIP1. We further show that a subset of senescence-associated miRNAs with the potential to target p21CIP1 is downregulated during [[DGCR8]]-mediated senescence. Interestingly, the antiproliferative response to miRNA biogenesis disruption is retained in human tumor cells, irrespective of p53 status. In summary, our results show that defective synthesis of canonical microRNAs results in cell-cycle arrest and cellular senescence in primary fibroblasts mediated by specific miRNAs, and thus identify global miRNA disruption as a novel senescence trigger. 
|mesh-terms=* Cell Growth Processes
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* Fibroblasts
* Gene Knockout Techniques
* HEK293 Cells
* Humans
* MicroRNAs
* Proteins
* RNA-Binding Proteins
* Tumor Suppressor Protein p53
* Up-Regulation
|keywords=* DGCR8
* fibroblasts
* microRNA
* p21CIP1
* p53
* senescence
|full-text-url=https://sci-hub.do/10.1111/acel.12117
}}