SRSF3 recruits DROSHA to the basal junction of primary microRNAs

Kim, Kijun; Nguyễn, Tùng Lâm; Li, Shaohua; Nguyen, Tuan Anh

doi:10.1261/rna.065862.118

Cited by 73 publications

(89 citation statements)

References 46 publications

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“…Closer investigation of the SRSF3 miRNA targets demonstrated ample SRSF3 binding within polycistronic miRNA clusters (Table S1), including miR-17-92 that was previously shown to be essential for proliferation and cell-renewal of embryonic stem (ES) cells (30). The overlapping roles of miR-17-92 and SRSF3 in promoting self-renewal (17,31), as well as previously reported role of SRSF3 in regulating miRNA processing (13,15) prompted us to further investigate the role of SRSF3 in miR-17-92 processing.…”

Section: Srsf3 Regulates Differential Processing Of Polycistronic Mirmentioning

confidence: 54%

“…According to previous studies, SRSF3 binding to a CNNC motif within a narrow window of 17-18nt downstream of the Drosha cleavage site is necessary and sufficient to enhance pri-miRNA processing (13,15). In mouse pluripotent stem cells, SRSF3 binding sites within the miR-17-92 cluster mapped downstream of miR-17 (CNNC at +18 from Drosha cleavage site), miR-18a (CNNC at +20), miR-19a (CNNC at +18) and miR-20a (CNNC at +18), each overlapping a CNNC motif within this window ( Fig.…”

Section: Srsf3 Regulates Differential Processing Of Polycistronic Mirmentioning

confidence: 99%

“…The nuclear microprocessor complex consisting of Drosha and two molecules of its co-factor DGCR8 cleaves the pri-primary (pri-)miRNAs to give rise to a ~60nt stem-loop pre-miRNAs (9,10). Specific sequence motifs within the pri-miRNA have been shown to affect the pri-miRNA cleavage efficiency, including the apical GUG/UGU, a GC and UG motifs 13nt and 14nt upstream of the Drosha cleavage site, respectively, and a CNNC motif 16-18nt/16-24nt downstream of the Drosha cleavage site (11)(12)(13)(14)(15). The CNNC motif was previously identified as the consensus binding motif for Serinearginine rich splicing factor 3 (SRSF3), an RNA binding protein (RBP) with multiple functions in mRNA metabolism (16,17).…”

Section: Introductionmentioning

confidence: 99%

“…The CNNC motif was previously identified as the consensus binding motif for Serinearginine rich splicing factor 3 (SRSF3), an RNA binding protein (RBP) with multiple functions in mRNA metabolism (16,17). In subsequent studies, binding of SRSF3 to the CNNC motif 17-18nt downstream of the Drosha cleavage site was shown to enhance the processing of pri-4 miR-30a/c and miR-16 (13,15). As 60% of the human miRNAs conserved to mouse contain a CNNC motif within this window (13), SRSF3 may play a broad role in modulating efficiency of pri-miRNA processing.…”

Section: Introductionmentioning

confidence: 99%

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SRSF3 confers selective processing of miR-17-92 cluster to promote tumorigenic properties in colorectal cancer

Ratnadiwakara

Engel

Jardé

et al. 2019

Preprint

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Almost a half of microRNAs (miRNAs) in mammalian cells are generated from polycistronic primary transcripts encoding more than one miRNA. Mature miRNAs from polycistronic clusters frequently regulate complementary sets of target mRNAs. How the processing of individual miRNAs within the clusters is controlled to give rise to distinct miRNA levels in vivo is not fully understood. Our investigation of SRSF3 (Serine-Arginine Rich Splicing Factor 3) regulated noncoding RNAs in pluripotent cells identified miR-17-92 cluster as a key SRSF3 target, SRSF3 binding to the CNNC motif 17-18nt downstream of the miRNA stem loop. Here we show that SRSF3 binding site context, not merely the distance from the stem loop, within primary transcript is a critical determinant of the processing efficiency of distinct miRNAs derived from the miR-17-92 cluster. SRSF3 specifically enhanced the processing of two paralog miRNAs, miR-17 and miR-20a, targeting overlapping mRNAs including the cell cycle inhibitor CDKN1A/p21. Functional analysis demonstrated that SRSF3 inhibits CDKN1A expression and promotes cell cycle and self-renewal through the miRNA processing pathway both in normal pluripotent stem cells and cancer cells. Strikingly, analysis of colorectal cancer tumour-normal pairs demonstrated that the SRSF3-regulated miRNA processing pathway is present in a large proportion of colorectal cancer patients and distinguishes poorly differentiated high-grade tumours. Our research uncovers a critical role of SRSF3 in selective processing of miR-17-92 miRNAs, which mechanistically and functionally links SRSF3 to hallmark features of cancer.

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Section: Srsf3 Regulates Differential Processing Of Polycistronic Mirmentioning

confidence: 54%

Section: Srsf3 Regulates Differential Processing Of Polycistronic Mirmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

SRSF3 confers selective processing of miR-17-92 cluster to promote tumorigenic properties in colorectal cancer

Ratnadiwakara

Engel

Jardé

et al. 2019

Preprint

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“…Additionally, TGF-β-stimulated SMAD may enhance the transcription of miRNA-coding genes by binding to their promoters (89,90). As shown in Figure 4, mutations may also affect the SRSF3-binding CNNC motif involved in pri-miRNA processing (91).…”

Section: Discussionmentioning

confidence: 99%

Somatic mutations in miRNA genes in lung cancer – potential functional consequences of non-coding sequence variants

Galka-Marciniak

Urbanek-Trzeciak

Nawrocka

et al. 2019

Preprint

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A growing body of evidence indicates that miRNAs may either drive or suppress oncogenesis. However, little is known about somatic mutations in miRNA genes. To determine the frequency and potential consequences of miRNA gene mutations, we analyzed whole exome sequencing datasets of ~500 lung adenocarcinoma (LUAD) and ~500 lung squamous cell carcinoma (LUSC) samples generated in the TCGA. Altogether, we identified >1000 mutations affecting ~500 different miRNA genes and showed that half of all cancers had at least one such mutation. Mutations occurred in most crucial parts of miRNA precursors, including mature miRNA and seed sequences. We showed that seed mutations strongly affected miRNA:target interactions, drastically changing the pool of predicted targets. Mutations may also affect miRNA biogenesis by changing the structure of miRNA precursors, DROSHA and DICER cleavage sites, and regulatory sequence/structure motifs. We identified 10 significantly overmutated hotspot miRNA genes, including the miR-379 gene in LUAD enriched in mutations in the mature miRNA and regulatory sequences. The occurrence of mutations in the hotspot miRNA genes was also shown experimentally. We present a comprehensive analysis of somatic mutations in miRNA genes and show that some of these genes are mutational hotspots, suggesting their potential role in cancer.3

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The transcribed ultraconserved region uc.160+ enhances processing and A‐to‐I editing of the miR‐376 cluster: hypermethylation improves glioma prognosis

et al. 2021

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Transcribed ultraconserved regions (T‐UCRs) are noncoding RNAs derived from DNA sequences that are entirely conserved across species. Their expression is altered in many tumor types, and, although a role for T‐UCRs as regulators of gene expression has been proposed, their functions remain largely unknown. Herein, we describe the epigenetic silencing of the uc.160+ T‐UCR in gliomas and mechanistically define a novel RNA–RNA regulatory network in which uc.160+ modulates the biogenesis of several members of the miR‐376 cluster. This includes the positive regulation of primary microRNA (pri‐miRNA) cleavage and an enhanced A‐to‐I editing on its mature sequence. As a consequence, the expression of uc.160+ affects the downstream, miR‐376‐regulated genes, including the transcriptional coregulators RING1 and YY1‐binding protein (RYBP) and forkhead box P2 (FOXP2). Finally, we elucidate the clinical impact of our findings, showing that hypermethylation of the uc.160+ CpG island is an independent prognostic factor associated with better overall survival in lower‐grade gliomas, highlighting the importance of T‐UCRs in cancer pathophysiology.

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SRSF3 recruits DROSHA to the basal junction of primary microRNAs

Cited by 73 publications

References 46 publications

SRSF3 confers selective processing of miR-17-92 cluster to promote tumorigenic properties in colorectal cancer

SRSF3 confers selective processing of miR-17-92 cluster to promote tumorigenic properties in colorectal cancer

Somatic mutations in miRNA genes in lung cancer – potential functional consequences of non-coding sequence variants

The transcribed ultraconserved region uc.160+ enhances processing and A‐to‐I editing of the miR‐376 cluster: hypermethylation improves glioma prognosis

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