Role of pri-miRNA tertiary structure in miR-17~92 miRNA biogenesis

Chaulk, Steven G.; Thede, Gina L.; Kent, Oliver A.; Xu, Zhaochun; Gesner, Emily M.; Veldhoen, Richard A.; Khanna, Suneil K.; Goping, Ing Swie; MacMillan, Andrew M.; Mendell, Joshua T.; Young, Howard S.; Fahlman, Richard P.; Glover, J. N. Mark

doi:10.4161/rna.8.6.17410

Cited by 88 publications

(106 citation statements)

References 58 publications

(76 reference statements)

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“…Interestingly, those pre-miRNAs (that is, miR-20a) that are located within the core of the tertiary structure are less efficiently processed. 28 The fact that TAF15 is mostly required for miR-20a biosynthesis suggests that TAF15 may be differentially required in respect to the tertiary structure of the cluster.…”

Section: Discussionmentioning

confidence: 99%

TAF15 is important for cellular proliferation and regulates the expression of a subset of cell cycle genes through miRNAs

et al. 2012

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1TAF15 (formerly TAFII68) is a member of the FET (FUS, EWS, TAF15) family of RNA-and DNA-binding proteins whose genes are frequently translocated in sarcomas. By performing global gene expression profiling, we found that TAF15 knockdown affects the expression of a large subset of genes, of which a significant percentage is involved in cell cycle and cell death. In agreement, TAF15 depletion had a growth-inhibitory effect and resulted in increased apoptosis. Among the TAF15-regulated genes, targets of microRNAs (miRNAs) generated from the onco-miR-17 locus were overrepresented, with CDKN1A/p21 being the top miRNAstargeted gene. Interestingly, the levels of onco-miR-17 locus coded miRNAs (miR-17-5p and miR-20a) were decreased upon TAF15 depletion and shown to affect the post-transcriptional regulation of TAF15-dependent genes, such as CDKN1A/p21. Thus, our results demonstrate that TAF15 is required to regulate gene expression of cell cycle regulatory genes post-transcriptionally through a pathway involving miRNAs. The findings that high TAF15 levels are needed for rapid cellular proliferation and that endogenous TAF15 levels decrease during differentiation strongly suggest that TAF15 is a key regulator of maintaining a highly proliferative rate of cellular homeostasis.Oncogene ( Keywords: FUS/EWS/TAF15 (FET) proteins; miRNAs; transcription; proliferation; neuronal differentiation; neuroblastoma INTRODUCTION TAF15 (formerly TAF II 68) is a nuclear protein known to associate with a distinct subpopulation of transcription factor IID (TFIID), a multi-subunit complex that nucleates the pre-initiation complex on the promoters of on protein-coding genes.1,2 As TAF15 was not found to be associated with all human TFIID complexes and has no ortholog in other non-vertebrate species, TAF15 is not considered a canonical TAF.3 TAF15 harbors a transcriptional activation domain, a RNA recognition motif and many Arg-Gly-Gly (RGG) repeats known to participate in RNA binding.1 TAF15 together with the related FUS and EWS constitutes the FET (FUS/EWS/TAF15) protein family whose genes are frequently translocated in sarcomas and rare hematopoietic and epithelial cancers. 4 In each case, the N-terminus of the proteins, containing a potent transcriptional activation domain, 5 is fused to the DNA-binding domain of a transcription factor to form oncogenic chimeras.

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Section: Discussionmentioning

confidence: 99%

TAF15 is important for cellular proliferation and regulates the expression of a subset of cell cycle genes through miRNAs

et al. 2012

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“…Here, we show that tertiary structure formation by primary miRNAs influences their processing into pre-miRNAs (Chaulk et al 2011). The phylogenetic sequence analysis of the pri-miR-17-92a transcript revealed that many interpre-miR regions, previously presumed to be nonfunctional since they do not contain the mature miRNA sequence, are also conserved.…”

Section: Discussionmentioning

confidence: 99%

“…During the submission of this work, Chaulk et al (2011) also showed complementary evidence of tertiary structure formation by pri-miR-17-92a at 2 nm resolution that showed a globular structure by Cryo EM. They addressed the effect of tertiary structure on processing in vitro using purified MPC components.…”

Section: Acknowledgmentsmentioning

confidence: 99%

Pri-miR-17-92a transcript folds into a tertiary structure and autoregulates its processing

Chakraborty

Mehtab²,

Patwardhan³

et al. 2012

RNA

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MicroRNAs control gene expression either by RNA transcript degradation or translational repression. Expressions of miRNAs are highly regulated in tissues, disruption of which leads to disease. How this regulation is achieved and maintained is still largely unknown. MiRNAs that reside on clustered or polycistronic transcripts represent a more complex case where individual miRNAs from a cluster are processed with different efficiencies despite being cotranscribed. To shed light on the regulatory mechanisms that might be operating in these cases, we considered the long polycistronic primary miRNA transcript pri-miR-17-92a that contains six miRNAs with diverse functions. The six miRNA domains on this cluster are differentially processed to produce varying amounts of resultant mature miRNAs in different tissues. How this is achieved is not known. We show, using various biochemical and biophysical methods coupled with mutational studies, that pri-miR-17-92a adopts a specific three-dimensional architecture that poses a kinetic barrier to its own processing. This tertiary structure could create suboptimal protein recognition sites on the pri-miRNA cluster due to higher-order structure formation.

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“…A cluster of microRNAs on human chromosome 13 has been found to be regulated by c-Myc, an important transcription factor that is overexpressed in many human cancers. And analysis of microRNA expression in over 300 individuals shows that microRNA profiles could be of value in cancer diagnosis (Chaulk et al, 2011;Zhao et al, 2013).…”

Section: Mirna and Cancer Diagnosismentioning

confidence: 99%