Alternative splicing affects the subcellular localization of Drosha

Link, Steffen; Grund, Stefanie; Diederichs, Sven

doi:10.1093/nar/gkw400

Cited by 50 publications

(50 citation statements)

References 65 publications

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“…Because GSK3b activity is regulated by various extracellular signals (Beurel et al, 2015), it is possible that serum starvation might cause an inhibition of GSK3b and mediate dephosphorylation of Ser 300/302 of Drosha, resulting in the accumulation in the cytoplasm. An alternatively spliced form of Drosha skipping exon 6, which encodes the putative nuclear localization signal, is reported to localize in both the cytoplasm and the nucleus (Dai et al, 2016;Link et al, 2016). However, the molecular size of cytoplasmic Drosha after serum starvation is equivalent to full-length Drosha (159 kDa) and indistinguishable from nuclear Drosha, thus it is unlikely that alternative splicing is involved in the change of nuclear/cytoplasmic ratio of Drosha upon serum starvation.…”

Section: Discussionmentioning

confidence: 99%

Control of ribosomal protein synthesis by Microprocessor complex

Jiang

Prabhakar

Voorn

et al. 2020

Preprint

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Ribosome biogenesis in eukaryotes requires stoichiometric production and assembly of 80 ribosomal proteins (RPs) and 4 ribosomal RNAs, and its rate must be coordinated with cellular growth. The indispensable regulator of RP biosynthesis is the 5'-terminal oligopyrimidine (TOP) motif, spanning the transcription start site of all RP genes. Here we show that the Microprocessor complex, previously linked to the first step of processing microRNAs (miRNAs), coregulates RP expression by binding the TOP motif of nascent RP mRNAs and stimulating transcription elongation via resolution of DNA/RNA hybrids. Cell growth arrest triggers nuclear export and degradation of the Microprocessor protein Drosha by the E3 ubiquitin ligase Nedd4, accumulation of DNA/RNA hybrids at RP gene loci, decreased RP synthesis, and ribosome deficiency, hence synchronizing ribosome production with cell growth. Conditional deletion of Drosha in erythroid progenitors phenocopies human ribosomopathies, in which ribosomal insufficiency leads to anemia. Outlining a miRNA-independent role of the Microprocessor complex at the interphase between cell growth and ribosome biogenesis offers a new paradigm by which cells alter their protein biosynthetic capacity and cellular metabolism.in response to the change in cellular growth environment remains to be identified (Meyuhas and Kahan, 2015; Patursky-Polischuk et al., 2014).During transcription, a three-stranded nucleic acid structure known as an R-loop spontaneously forms(García-Muse and Aguilera, 2019). It is composed of a DNA/RNA hybrid (a single-stranded template DNA (ssDNA) hybridized with a nascent mRNA) and an associated non-template ssDNA (García-Muse and Aguilera, 2019;Sanz and Chédin, 2019;Sanz et al., 2016). R-loops are critical modulator of gene expression and DNA repair (García-Muse and Aguilera, 2019;Sanz and Chédin, 2019;Sanz et al., 2016), and their extended persistence during transcription is inhibitory to gene expression (Gowrishankar et al., 2013;Nudler, 2012). The abundance of R-loops is determined by the balance between its formation and resolution of DNA/RNA hybrids and various factors, including transcription factors, helicases, ribonucleases, topoisomerases, chromatin remodelers, proteins in DNA repair and RNA surveillance, have been identified to control R-loop homeostasis(García-Muse and Aguilera, 2019). Deregulation of R-loops, which results in aberrant gene expression and chromatin structure, increased DNA breaks, and genome instability, contributes to human disease, including neurological disorders and tumorigenesis (García-Muse and Aguilera, 2019;Groh and Gromak, 2014;Sanz et al., 2016).The Microprocessor complex comprises two core components, the ribonuclease (RNase) III Drosha and its cofactor Dgcr8. It is essential for the biogenesis of most microRNAs (miRNAs), short RNAs that repress gene expression by binding to messenger RNAs and targeting them for degradation and/or preventing their translation (Han et al., 2004;Siomi and Siomi, 2010). The Microprocessor localizes predom...

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Section: Discussionmentioning

confidence: 99%

Control of ribosomal protein synthesis by Microprocessor complex

Jiang

Prabhakar

Voorn

et al. 2020

Preprint

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“…Pri-miRNA increase may reflect an increase in mRNA resulting from the decrease in cleavage of the miRNA from exons in the Drosha KO cells. Finally, a recent study showed that the pri-miRNA processing efficiency is not correlated with the expression level of cytoplasmic Drosha isoform (52). We demonstrated that c-Drosha exists and is capable of processing pri-miRNA.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Drosha activity generated by alternative splicing

et al. 2016

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RNase III enzyme Drosha interacts with DGCR8 to form the Microprocessor, initiating canonical microRNA (miRNA) maturation in the nucleus. Here, we re-evaluated where Drosha functions in cells using Drosha and/or DGCR8 knock out (KO) cells and cleavage reporters. Interestingly, a truncated Drosha mutant located exclusively in the cytoplasm cleaved pri-miRNA effectively in a DGCR8-dependent manner. In addition, we demonstrated that in vitro generated pri-miRNAs when transfected into cells could be processed to mature miRNAs in the cytoplasm. These results indicate the existence of cytoplasmic Drosha (c-Drosha) activity. Although a subset of endogenous pri-miRNAs become enriched in the cytoplasm of Drosha KO cells, it remains unclear whether pri-miRNA processing is the main function of c-Drosha. We identified two novel in-frame Drosha isoforms generated by alternative splicing in both HEK293T and HeLa cells. One isoform loses the putative nuclear localization signal, generating c-Drosha. Further analysis indicated that the c-Drosha isoform is abundant in multiple cell lines, dramatically variable among different human tissues and upregulated in multiple tumors, suggesting that c-Drosha plays a unique role in gene regulation. Our results reveal a new layer of regulation on the miRNA pathway and provide novel insights into the ever-evolving functions of Drosha.

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“…Whilst the middle and the C-terminal domain are important for pri-miRNA processing and DGCR8 binding, the activity of the N-terminus remains mysterious. Different investigations have linked this region to the subcellular localization of Drosha, stabilization, and response to tension [62]. The repression occurs solely in mature miRNAs and not in pri-miRNA transcripts, evidencing that the Drosha E1147K mutation affects processing of pri-miRNAs.…”

Section: Dicermentioning

confidence: 99%

ROLE OF COMPONENTS OF microRNA MACHINERY IN CARCINOGENESIS

Kian¹,

Moradi²,

Ghorbian³

2018

Exp. Onc.

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MicroRNAs (miRNAs) are a broad class of non-coding RNAs nearly 21 nucleotides length, which play crucial functions in posttranscriptional gene regulation. These molecules are associated with many developmental and cellular processes in eukaryotic organisms. Current investigation has reported major factors contributing to miRNA biogenesis and has constituted basic principles of miRNA function. More recently, it was confirmed that various miRNAs are clearly implicated in human malignancies, such as lung, breast, ovarian, bladder, colon cancer and other kinds of carcinoma. In addition, dysregulation in the miRNA machinery elements such as Dicer, Drosha, DGCR8, Argonaut, and TRBP could be involved in the progress of many tumor types. The purpose of the current review was to compile growing information besides how miRNA biogenesis and gene silencing are modified to develop cancer.

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Alternative splicing affects the subcellular localization of Drosha

Cited by 50 publications

References 65 publications

Control of ribosomal protein synthesis by Microprocessor complex

Control of ribosomal protein synthesis by Microprocessor complex

Cytoplasmic Drosha activity generated by alternative splicing

ROLE OF COMPONENTS OF microRNA MACHINERY IN CARCINOGENESIS

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