BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex

Kawai, Shinji; Amano, Atsuo

doi:10.1083/jcb.201110008

Cited by 164 publications

(121 citation statements)

References 30 publications

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“…Additionally, BRCA1, a key player in DSBs (Double Strand Breaks) response, has been recently shown to increase the expression of let-7a-1, miR-16-1, miR-145, and miR-34a through a direct binding of p68 RNA helicase in Drosha complex [83].…”

Section: Ber Enzymes and Mirna Regulation: A New Paradigm In Gene Expmentioning

confidence: 99%

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Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

2017

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Section: Ber Enzymes and Mirna Regulation: A New Paradigm In Gene Expmentioning

confidence: 99%

“…ATM, a crucial kinase in DDR, regulates miRNA expression in response to DNA damage through the phosphorylation of different targets including, KSPR [84], p53 [84,85], ΔNp63α [86] and BRCA1 by indirectly promoting the processing of a subset of pri-miRNAs [83].…”

Section: Ber Enzymes and Mirna Regulation: A New Paradigm In Gene Expmentioning

confidence: 99%

Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

2017

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“…While the positive regulatory machinery of miRNA processing is relatively well understood (28,39), negative regulation of the pathway is largely uncharacterized. Our results demonstrate a negative regulation of miRNA processing exerted by COX-2 through DDX5.…”

Section: Discussionmentioning

confidence: 99%

Regulation of MicroRNA 183 by Cyclooxygenase 2 in Liver Is DEAD-Box Helicase p68 (DDX5) Dependent: Role in Insulin Signaling

Motiño

Francés

Mayoral

et al. 2015

Molecular and Cellular Biology

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g Cyclooxygenase (COX) catalyzes the first step in prostanoid biosynthesis and exists as two isoforms. COX-1 is a constitutive enzyme involved in physiological processes, whereas COX-2 is induced by a variety of stimuli. MicroRNAs (miRNAs) are noncoding RNAs that function as key posttranscriptional regulators of gene expression. Although it is known that COX-2 expression is regulated by miRNAs, there are no data regarding COX-2 involvement in miRNA regulation. Considering our previous results showing that COX-2 expression in hepatocytes protects against insulin resistance, we evaluated the role of COX-2 in the regulation of a specific set of miRNAs implicated in insulin signaling in liver cells. Our results provide evidence of the molecular basis for a novel function of COX-2 in miRNA processing. COX-2 represses miRNA 23b (miR-23b), miR-146b, and miR-183 expression in liver cells by increasing the level of DEAD-box helicase p68 (DDX5) through phosphatidylinositol 3-kinase (PI3K)/p300 signaling and by modulating the enzymatic function of the Drosha (RNase type III) complex through its physical association with DDX5. The decrease of miR-183 expression promotes protection against insulin resistance by increasing insulin receptor substrate 1 (IRS1) levels. These results indicate that the modulation of miRNA processing by COX-2 is a key event in insulin signaling in liver and has potential clinical implications for the management of various hepatic dysfunctions. Cyclooxygenase 1 (COX-1) and 2 catalyze the first step in prostanoid biosynthesis. COX-1 (PTGS1) is constitutively expressed in many tissues, whereas COX-2 (PTGS2) expression is induced by a variety of stimuli such as growth factors, proinflammatory stimuli, hormones, and other cellular stresses (1-3). We and others have demonstrated that partial hepatectomy (PH) induced COX-2 expression in hepatocytes and contributed to the progression of the cell cycle during regeneration (4, 5). In addition to liver regeneration after PH or exposure to hepatotoxic agents, expression of COX-2 has been detected in animal models of cirrhosis (6), in human hepatoma cell lines (7,8), in human hepatocellular carcinoma (HCC) (9), and after hepatitis B virus (HBV) and hepatitis C virus (HCV) infection (10, 11). Further, overexpression of COX-2 in liver exerts efficient protection against acute liver injury by an antiapoptotic/antinecrotic effect and by accelerated early hepatocyte proliferation (12, 13).Insulin resistance (IR) plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). Our previous results from studies performed in a model of transgenic mice constitutively expressing human COX-2 in hepatocytes (hCOX-2-Tg) indicate a protective role of COX-2 in a model of insulin resistance induced by a high-fat diet (HFD) (14) and in liver damage induced by hyperglycemia (15).MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate their target genes primarily through RNA destabilization or t...

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“…One miR whose biogenesis is enhanced by SMAD is miR-21, which targets several tumour-suppressor genes including PTEN, therefore may act as an oncomiR (Kumarswamy et al 2011). Also BRCA1, which is vital for maintenance of genomic stability, increased the levels of mature cancer-associated miRs including let7a-1, miR-16-1 and miR-34a via a mechanism involving direct association of BRCA1 with Drosha and pri-miRs through recognition of branched secondary structures (Kawai & Amano 2012). Processing of the BRCA1-regulated miR subset is likely to be lost in BRCA1-mutant cells, perhaps a mechanism by which BRCA1 mutation enhances tumourigenesis.…”

Section: Mir-specific Regulation By Microprocessormentioning

confidence: 99%

“…It is also possible that SRA could sequester RISC components away from their pre-miR substrates to regulate RISC activity. It is feasible that other proteins may fulfil similar roles to SRA in coupling NR transcriptional activity with Drosha Microprocessormediated pri-miR cleavage, since both FUS, a Microprocessor component that stimulates pri-miR processing (Morlando et al 2012), and p68, known to promote cleavage of a subset of pri-miRs (Fukuda et al 2007, Salzman et al 2007, Kawai & Amano 2012, Samaan et al 2013, are known AR cofactors (Clark et al 2008, Haile et al 2011). …”

Section: Nuclear Risc Components As Coactivators Of Era and Armentioning

confidence: 99%

Interplay between steroid signalling and microRNAs: implications for hormone-dependent cancers

Fletcher¹,

Dart²,

Bevan³

2014

Endocrine Related Cancer

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Hormones are key drivers of cancer development. To date, interest has largely been focussed on the classical model of hormonal gene regulation, but there is increasing evidence for a role of hormone signalling pathways in post-translational regulation of gene expression. In particular, a complex and dynamic network of bi-directional interactions with microRNAs (miRs) at all stages of biogenesis and during target gene repression is emerging. miRs, which act mainly by negatively regulating gene expression through association with 3 0 -UTRs of mRNA species, are increasingly understood to be important in development, normal physiology and pathogenesis. Given recent demonstrations of altered miR profiles in a diverse range of cancers, their ability to function as oncogenes or tumour suppressors, and hormonal regulation of miRs, understanding mechanisms by which miRs are generated and regulated is vitally important. miRs are transcribed by RNA polymerase II and then processed in the nucleus by the Drosha-containing Microprocessor complex and in the cytoplasm by Dicer, before mature miRs are incorporated into the RNA-induced silencing complex. It is increasingly evident that multiple cellular signalling pathways converge upon the miR biogenesis cascade, adding further layers of regulatory complexity to modulate miR maturation. This review summarises recent advances in identification of novel components and regulators of the Microprocessor and Dicer complexes, with particular emphasis on the role of hormone signalling pathways in regulating their activity. Understanding hormone regulation of miR production and how this is perturbed in cancer are critical for the development of miR-based therapeutics and biomarkers.

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BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex

Abstract: The BRCA1 tumor suppressor associates with both the DROSHA microRNA maturation complex and primary miRNA transcripts, and promotes transcript processing.

Cited by 164 publications

References 30 publications

Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

Regulation of MicroRNA 183 by Cyclooxygenase 2 in Liver Is DEAD-Box Helicase p68 (DDX5) Dependent: Role in Insulin Signaling

Interplay between steroid signalling and microRNAs: implications for hormone-dependent cancers

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