Inactivating mutations in Drosha mediate vascular abnormalities similar to hereditary hemorrhagic telangiectasia

Jiang, Xuan; Wooderchak-Donahue, Whitney; McDonald, Jamie; Ghatpande, Prajakta; Baalbaki, Mai; Sandoval, Melissa; Hart, Daniel; Clay, Hilary; Coughlin, Shaun R.; Lagna, Giorgio; Bayrak-Toydemir, Pınar; Hata, Akiko

doi:10.1126/scisignal.aan6831

Cited by 24 publications

(35 citation statements)

References 47 publications

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“…The tissue-specific manifestation of physical abnormalities in DBA suggests a differential susceptibility to ribosome abnormalities or insufficiency of each cell type, presumably due to specific demands on protein synthesis. For example, we found that erythropoiesis is more severely impaired than vascular development in Drosha cKO mice (Jiang et al, 2017;Jiang et al, 2018). We speculate that erythrocyte progenitors, rapidly proliferating with high demand for Gata1 and globin protein synthesis, are more susceptible to ribosome shortages than endothelial cells.…”

Section: Discussionmentioning

confidence: 73%

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: 73%

Control of ribosomal protein synthesis by Microprocessor complex

Jiang

Prabhakar

Voorn

et al. 2020

Preprint

Self Cite

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“…A study by Jiang et al identified a higher prevalence of Drosha mutations in an HHT population and generated robust Drosha knockout animal models. Exome sequencing was performed on a total of 98 individuals; 23 confirmed HHT patients and 75 probands suspected to have HHT who lacked known pathogenic mutations [ 95 ]. Three heterozygous Drosha mutations (P32L, P100L and K226E) were detected in seven of the 98 individuals (~7%) compared with 0.04% in the general population [ 93 ].…”

Section: Mirs As Pathogenic Factors In Hhtmentioning

confidence: 99%

“…An additional Drosha mutant (R279L) was found in a separate HHT family [ 93 ]. These Drosha mutants were analyzed in mouse embryonic fibroblasts (MEFs); interestingly, only the P100L and R279L mutants were shown to reduce expression of specific miRs, by approximately 17% and 35%, respectively, compared to wild type (WT) [ 95 ]. P100L and R279L were introduced into zebrafish embryos to investigate their angiogenic functions.…”

Section: Mirs As Pathogenic Factors In Hhtmentioning

confidence: 99%

“…P100L and R279L were introduced into zebrafish embryos to investigate their angiogenic functions. Zebrafish with these two mutants developed vascular defects, including vascular permeability and a reduction of vascular density [ 95 ]. An EC-specific inducible knockout Drosha mouse model also demonstrated vascular permeability, disorganized vasculature and, interestingly, intestinal bleeding [ 95 ].…”

Section: Mirs As Pathogenic Factors In Hhtmentioning

confidence: 99%

“…Zebrafish with these two mutants developed vascular defects, including vascular permeability and a reduction of vascular density [ 95 ]. An EC-specific inducible knockout Drosha mouse model also demonstrated vascular permeability, disorganized vasculature and, interestingly, intestinal bleeding [ 95 ]. However, no AVMs were detected in either animal model [ 95 ].…”

Section: Mirs As Pathogenic Factors In Hhtmentioning

confidence: 99%

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Non-Coding RNAs and Hereditary Hemorrhagic Telangiectasia

Cannavicci

Zhang

Kutryk

2020

JCM

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Non-coding RNAs (ncRNAs) are functional ribonucleic acid (RNA) species that include microRNAs (miRs), a class of short non-coding RNAs (∼21–25 nucleotides), and long non-coding RNAs (lncRNAs) consisting of more than 200 nucleotides. They regulate gene expression post-transcriptionally and are involved in a wide range of pathophysiological processes. Hereditary hemorrhagic telangiectasia (HHT) is a rare disorder inherited in an autosomal dominant fashion characterized by vascular dysplasia. Patients can develop life-threatening vascular malformations and experience severe hemorrhaging. Effective pharmacological therapies are limited. The study of ncRNAs in HHT is an emerging field with great promise. This review will explore the current literature on the involvement of ncRNAs in HHT as diagnostic and pathogenic factors.

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DROSHA but not DICER is required for human haematopoietic stem cell function

Walpole

Gooneratne

et al. 2022

Clin & Trans Imm

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Objectives DROSHA and DICER have central roles in the biogenesis of microRNAs (miRNAs). However, we previously showed that in the murine system, DROSHA has an alternate function where it directly recognises and cleaves protein‐coding messenger (m)RNAs and this is critical for safeguarding the pluripotency of haematopoietic stem cells (HSCs). Maintenance of murine HSC function is dependent on DROSHA‐mediated cleavage of two mRNAs, Myl9 and Todr1. The goal of this study is to determine whether this pathway is conserved in human HSCs. Methods DROSHA and DICER were knocked down in human cord blood CD34+ HSCs with short hairpin RNAs. The function of HSCs was analysed in vitro and in humanised mice. Analysis of mRNA cleavage was performed by capture of 5′ phosphorylated RNAs. Results Consistent with murine HSCs, DROSHA knockdown impaired the differentiation of human HSCs in vitro and engraftment into humanised mice, whereas DICER knockdown had no impact. DROSHA cleaves the MYL9 mRNA in human HSCs and DROSHA deficiency resulted in the accumulation of the mRNA. However, ectopic expression of MYL9 did not impair human HSC function. We were unable to identify a human homolog of Todr1. Conclusion A miRNA‐independent function of DROSHA is critical for the function of human HSCs. DROSHA directly recognises and degrades mRNAs in humans HSCs. However, unlike in murine HSCs, the degradation of the MYL9 mRNA alone is not critical for human HSC function. Therefore, DROSHA must be inhibiting other targets and/or has another miRNA‐independent function that is essential for safeguarding the pluripotency of human HSCs.

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Inactivating mutations in Drosha mediate vascular abnormalities similar to hereditary hemorrhagic telangiectasia

Cited by 24 publications

References 47 publications

Control of ribosomal protein synthesis by Microprocessor complex

Control of ribosomal protein synthesis by Microprocessor complex

Non-Coding RNAs and Hereditary Hemorrhagic Telangiectasia

DROSHA but not DICER is required for human haematopoietic stem cell function

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