Extensive post-transcriptional regulation of microRNAs and its implications for cancer

Thomson, J. Michael; Newman, Martin A.; Parker, Joel S.; Morin‐Kensicki, Elizabeth; Wright, Tricia M.; Hammond, Scott M.

doi:10.1101/gad.1444406

Cited by 813 publications

(671 citation statements)

References 33 publications

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“…First, it has been reported that, during development and in tumors, the processing efficiency of pri-miRNAs is decreased. 32 However, the mRNA levels of Drosha and DGCR8 are not induced concordantly with the production of mature miRNAs. Post-translational regulation of DGCR8 activity mediated by dimerization and heme binding may explain this apparent discrepancy.…”

Section: Discussionmentioning

confidence: 95%

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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Section: Discussionmentioning

confidence: 95%

Structure of the dimerization domain of DiGeorge Critical Region 8

et al. 2010

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“…By contrast, the pri-form of the highly retinal-enriched miR-96/182/ 183 cluster is barely detectable even by RT-PCR, so abundance of some primiRNAs is unlikely to reflect general deficiencies in miRNA processing in retina . It is not yet clear what role, if any, these abundant primiRNAs may be playing in the retina, although high levels of other unprocessed pri-miRNAs have also recently been observed in embryonic tissue and cancer cells (Thomson et al, 2006), and this has led to the proposal that primiRNA processing by Drosha may be regulated in certain circumstances (Wulczyn et al, 2007). The recent discovery that activated Smads can associate with the Drosha complex and regulate its activity suggests a possible mechanism by which this could occur.…”

Section: Regulated Processing Of Retinal Pri-mirnas?mentioning

confidence: 99%

New meaning in the message: Noncoding RNAs and their role in retinal development

Rapicavoli

Blackshaw

2009

Developmental Dynamics

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Recent studies have indicated that non-protein-coding RNAs (ncRNAs) may play prominent and diverse roles in the development of the nervous system. These ncRNAs are now known to perform a broad range of cellular functions, and in particular appear to be prominent players in the regulation of transcription and translation. In this review, we discuss recent advances in our understanding of the role of ncRNAs in vertebrate retinal development. Noncoding RNAs that are known or suspected to play a functional role in the specification and maturation of retinal cell subtypes include miRNAs, long noncoding opposite-strand transcripts (OSTs), and other long ncRNAs such as Tug1 and RNCR2. Though the mechanism of action of most of these ncRNAs is still largely unclear, it is likely that these molecules represent a major, and thus far largely unappreciated, component of the molecular machinery involved in retinal cell fate specification.

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“…However, a majority of micro-RNAs are downregulated in tumor tissues, probably reflecting the cellular dedifferentiation generally associated with transformation (Lu et al, 2005). This downregulation is due at least in part to impairment of the microprocessor function (Thomson et al, 2006). Among these downregulated micro-RNAs, several have been shown to be bona fide tumor suppressors (Calin et al, 2002;Mayr et al, 2007;Welch et al, 2007;Bonci et al, 2008;Cole et al, 2008;Esquela-Kerscher et al, 2008;Chen et al, 2009;Trang et al, 2010).…”

Section: Introductionmentioning

confidence: 99%