The Drosha-DGCR8 complex in primary microRNA processing

Han, Jinju; Lee, Yoontae; Yeom, Kyu-Hyun; Kim, Young‐Kook; Jin, Hua; Kim, V. Narry

doi:10.1101/gad.1262504

Cited by 1,885 publications

(1,453 citation statements)

References 34 publications

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“…28 DGCR8, which can directly interact with pri-miRNA, assists this process by correctly positioning Drosha on the pri-miRNA. 29 Other proteins, including Lin28, nuclear ribonucleoprotein (hnRNP) A1, R-Smads, p53 and BRCA1, interact with Drosha and specifically regulate the processing of a group of pri-miRNA. Lin28 and hnRNP A1 interact with Drosha by binding to the terminal loop region of pri-let-7 and pri-miR-18a, respectively.…”

Section: Discussionmentioning

confidence: 99%

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

et al. 2016

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Radioresistance is a major obstacle in successful clinical cancer radiotherapy, and the underlying mechanisms are not clear. Here we show that IKKα-mediated miR-196a biogenesis via interaction with Drosha regulates the sensitivity of nasopharyngeal carcinoma (NPC) cells to radiotherapy. Phosphorylation of IKKα at T23 site (p-IKKαT23) promotes the binding of IKKα to Drosha that accelerates the processing of miR-196a primary transcripts, leading to increased expressions of both precursor and mature miR-196a. Dephosphorylation of p-IKKαT23 downregulates miR-196a expression and promotes the resistance of NPC cells to radiation treatment. The miR-196a mimic suppresses while its inhibitor promotes the resistance of NPC to radiation treatment. Importantly, the expression of p-IKKαT23 is positively related to the expression of miR-196a in human NPC tissues, and expression of p-IKKαT23 and miR-196a is inversely correlated with NPC clinical radioresistance. Thus, our studies establish a novel mechanistic link between the inactivation of IKKαT23-Drosha-miR-196a pathway and NPC radioresistance, and de-inactivation of IKKαT23-Drosha-miR-196a pathway would be an efficient way to restore the sensitivity of radioresistant NPC to radiotherapy.

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Section: Discussionmentioning

confidence: 99%

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

et al. 2016

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“…[8][9][10] In the first step, a pri-miRNA is cleaved into a $65-nt intermediate, termed precursor miRNAs (pre-miRNAs), by the combined action of an RNase III enzyme Drosha 11 and an RNA-binding protein DiGeorge critical region 8 (DGCR8; the name in mammals; its fly and worm homologs are called Pasha and Pash-1, respectively). [11][12][13][14][15] DGCR8 and Drosha form a complex termed the Microprocessor. The pre-miRNA is then transported to the cytoplasm and is further cleaved by Dicer, another RNase III enzyme, to give a duplex.…”

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confidence: 99%

Structure of the dimerization domain of DiGeorge Critical Region 8

et al. 2010

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Maturation of microRNAs (miRNAs,~22nt) from long primary transcripts [primary miRNAs (pri-miRNAs)] is regulated during development and is altered in diseases such as cancer. The first processing step is a cleavage mediated by the Microprocessor complex containing the Drosha nuclease and the RNA-binding protein DiGeorge critical region 8 (DGCR8). We previously reported that dimeric DGCR8 binds heme and that the heme-bound DGCR8 is more active than the heme-free form. Here, we identified a conserved dimerization domain in DGCR8. Our crystal structure of this domain (residues 298-352) at 1.7 Å resolution demonstrates a previously unknown use of a WW motif as a platform for extensive dimerization interactions. The dimerization domain of DGCR8 is embedded in an independently folded heme-binding domain and directly contributes to association with heme. Heme-binding-deficient DGCR8 mutants have reduced pri-miRNA processing activity in vitro. Our study provides structural and biochemical bases for understanding how dimerization and heme binding of DGCR8 may contribute to regulation of miRNA biogenesis.

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“…To become mature, miRNAs need to undergo several post‐transcriptional modifications. Initially, the miRNA is transcribed by RNA polymerase II as a large primary transcript (>1 kb) called “pri‐miRNA.” The pri‐miRNA is recognized by the microprocessor complex, which contains DGCR8 and the RNase III enzyme Drosha (Denli, Tops, Plasterk, Ketting & Hannon, 2004; Han et al., 2004). In the nucleus, Drosha cleaves the pri‐miRNA into a 70 nt stem‐loop precursor called “pre‐miRNA” (Lee et al., 2003).…”

Section: Micrornasmentioning

confidence: 99%

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

et al. 2018

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SummaryHereditary and sporadic laminopathies are caused by mutations in genes encoding lamins, their partners, or the metalloprotease ZMPSTE24/FACE1. Depending on the clinical phenotype, they are classified as tissue‐specific or systemic diseases. The latter mostly manifest with several accelerated aging features, as in Hutchinson–Gilford progeria syndrome (HGPS) and other progeroid syndromes. MicroRNAs are small noncoding RNAs described as powerful regulators of gene expression, mainly by degrading target mRNAs or by inhibiting their translation. In recent years, the role of these small RNAs has become an object of study in laminopathies using in vitro or in vivo murine models as well as cells/tissues of patients. To date, few miRNAs have been reported to exert protective effects in laminopathies, including miR‐9, which prevents progerin accumulation in HGPS neurons. The recent literature has described the potential implication of several other miRNAs in the pathophysiology of laminopathies, mostly by exerting deleterious effects. This review provides an overview of the current knowledge of the functional relevance and molecular insights of miRNAs in laminopathies. Furthermore, we discuss how these discoveries could help to better understand these diseases at the molecular level and could pave the way toward identifying new potential therapeutic targets and strategies based on miRNA modulation.

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The Drosha-DGCR8 complex in primary microRNA processing

Cited by 1,885 publications

References 34 publications

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

Structure of the dimerization domain of DiGeorge Critical Region 8

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

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