Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs

Brameier, Markus; Herwig, Astrid; Reinhardt, Richard; Walter, Lutz; Gruber, Jens

doi:10.1093/nar/gkq776

Cited by 276 publications

(276 citation statements)

References 60 publications

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“…Consistent with our observations, Brameier et al (70) found that SNORD27 [designated as U27 sno-miRNA (for snoRNA derived microRNA)] generates short stable fragments of ∼20 nt in length. However, the physiological function of these fragments remains unclear, because U27 sno-miRNA did not cause an effect in a Renilla/Luciferase reporter system in HeLa cells.…”

Section: Discussionsupporting

confidence: 92%

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Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing

Falaleeva

Pagès

Matuszek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

171

152

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C/D box small nucleolar RNAs (SNORDs) are small noncoding RNAs, and their best-understood function is to target the methyltransferase fibrillarin to rRNA (for example, SNORD27 performs 2′-Omethylation of A27 in 18S rRNA). Unexpectedly, we found a subset of SNORDs, including SNORD27, in soluble nuclear extract made under native conditions, where fibrillarin was not detected, indicating that a fraction of the SNORD27 RNA likely forms a protein complex different from canonical snoRNAs found in the insoluble nuclear fraction. As part of this previously unidentified complex, SNORD27 regulates the alternative splicing of the transcription factor E2F7 pre-mRNA through direct RNA-RNA interaction without methylating the RNA, likely by competing with U1 small nuclear ribonucleoprotein (snRNP). Furthermore, knockdown of SNORD27 activates previously "silent" exons in several other genes through base complementarity across the entire SNORD27 sequence, not just the antisense boxes. Thus, some SNORDs likely function in both rRNA and pre-mRNA processing, which increases the repertoire of splicing regulators and links both processes.alternative splicing | gene regulation | snoRNAs | pre-mRNA processing S mall nucleolar RNAs (snoRNAs) are 60-to 300-nt-long noncoding RNAs that accumulate in the nucleolus. Based on conserved sequence elements, snoRNAs are classified as C/D box small nucleolar RNAs (SNORDs) or H/ACA box snoRNAs (SNORAs). SNORDs contain sequence elements termed C (RUGAUGA) and D (CUGA) boxes, usually present in duplicates (C′ and D′ boxes), and up to two antisense boxes that hybridize to the target RNA (1). In humans, SNORDs are usually derived from introns. After the splicing reaction, introns are excised as lariats, which are then opened by the debranching enzyme and subsequently degraded. Intronic SNORDs escape this degradation by forming a protein complex that consists of non-histone chromosome protein 2-like 1 (NHP2L1, 15.5K, SNU13), nucleolar protein 5A (NOP56), nucleolar protein 5 (NOP58), and fibrillarin (2-4). The SNORD protein complex forms through the entry of the snoRNA and fibrillarin to a complex containing NHP2L1, NOP58, and at least five assembly factors (5). The SNORD acts as a scaffold for the final protein complex formation and also controls recognition of other RNAs using the antisense boxes. The antisense boxes recognize sequences in rRNA, resulting in the fifth nucleotide upstream of the D or D′ box being 2′-O-methylated by fibrillarin (1). Structural studies indicate that the active form of SNORDs is dimeric (6).The conserved overall structure of SNORDs allows the identification of their putative target RNA binding sites. However, numerous SNORDs without obvious target RNAs have been identified (7-10) and are termed "orphan snoRNAs." Genome-wide deep sequencing experiments identified shorter but stable SNORD fragments that were found in all species tested, ranging from mammals to the protozoan Giardia lamblia (11) and EpsteinBarr virus (12). Fragments longer than 27 nt generated by SNORDs will ...

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Section: Discussionsupporting

confidence: 92%

“…Several SNORDs and H/ACA box snoRNAs have been shown to be precursors for microRNAs (69,70). Consistent with our observations, Brameier et al (70) found that SNORD27 [designated as U27 sno-miRNA (for snoRNA derived microRNA)] generates short stable fragments of ∼20 nt in length.…”

Section: Discussionsupporting

confidence: 90%

Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing

Falaleeva

Pagès

Matuszek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

171

152

View full text Add to dashboard Cite

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“…In PCa, snoRNA U50 has been reported to be a candidate tumor-suppressor gene and a mutation in its sequence has been associated with clinically significant disease (Dong et al, 2008). Recent findings have demonstrated that discrete in size snoRNA fragments are produced from a vast majority of snoRNA loci (Taft et al, 2009) and that they can also function as miRNAs The small transcriptome of prostate cancer ES Martens-Uzunova et al (Ender et al, 2008;Brameier et al, 2011). Additional research is needed to investigate whether this unconventional function of snoRNAs is a wide spread mechanism of gene regulation and whether this holds true for snoRNAs identified in this study.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer

et al. 2011

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Prostate cancer (PCa) is the most frequent male malignancy and the second most common cause of cancer-related death in Western countries. Current clinical and pathological methods are limited in the prediction of postoperative outcome. It is becoming increasingly evident that small non-coding RNA (ncRNA) species are associated with the development and progression of this malignancy. To assess the diversity and abundance of small ncRNAs in PCa, we analyzed the composition of the entire small transcriptome by Illumina/ Solexa deep sequencing. We further analyzed the micro-RNA (miRNA) expression signatures of 102 fresh-frozen patient samples during PCa progression by miRNA microarrays. Both platforms were cross-validated by quantitative reverse transcriptase-PCR. Besides the altered expression of several miRNAs, our deep sequencing analyses revealed strong differential expression of small nucleolar RNAs (snoRNAs) and transfer RNAs (tRNAs). From microarray analysis, we derived a miRNA diagnostic classifier that accurately distinguishes normal from cancer samples. Furthermore, we were able to construct a PCa prognostic predictor that independently forecasts postoperative outcome. Importantly, the majority of miRNAs included in the predictor also exhibit high sequence counts and concordant differential expression in Illumina PCa samples, supported by quantitative reverse transcriptase-PCR. Our findings provide miRNA expression signatures that may serve as an accurate tool for the diagnosis and prognosis of PCa.

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“…GAS5 is a 5′-terminal oligopyrimidine tract (5′-TOP) gene, and comprises 12 exons which are alternatively spliced to yield two possible mature lncRNAs [11]. GAS5 intronic sequence additionally encodes ten distinct box C/D snoRNAs [11]; three of which (U44, U74 and U78) may serve as miRNA precursors [12]. Multiple other GAS5 expressed sequence tags (ESTs) have also been identified, many of which contain retained introns, indicating that posttranscriptional processing of GAS5 RNA is complex.…”

Section: Introductionmentioning

confidence: 99%

Regulation of apoptosis by long non-coding RNA GAS5 in breast cancer cells: implications for chemotherapy

Pickard

Williams

2014

Breast Cancer Res Treat

153

136

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Purpose: The putative tumour suppressor and apoptosis-promoting gene, growth arrestspecific 5 (GAS5), encodes lncRNA and snoRNAs. Its expression is down-regulated in breast cancer, which adversely impacts patient prognosis. In this preclinical study, the consequences of decreased GAS5 expression for breast cancer cell survival following treatment with chemotherapeutic agents are addressed. In addition, functional responses of triple-negative breast cancer cells to GAS5 lncRNA are examined, and mTOR inhibition as a strategy to enhance cellular GAS5 levels is investigated. Methods: Breast cancer cell lines were transfected with either siRNA to GAS5 or with a plasmid encoding GAS5 lncRNA and the effects on breast cancer cell survival were determined. Cellular responses to mTOR inhibitors were evaluated by assaying culture growth and GAS5 transcript levels. Results: GAS5 silencing attenuated cell responses to apoptotic stimuli, including classical chemotherapeutic agents; the extent of cell death was directly proportional to cellular GAS5 levels. Imatinib action in contrast, was independent of GAS5. GAS5 lncRNA promoted the apoptosis of triple-negative and estrogen receptor-positive cells but only dual PI3K/mTOR inhibition was able to enhance GAS5 levels in all cell types. Conclusions: Reduced GAS5 expression attenuates apoptosis induction by classical chemotherapeutic agents in breast cancer cells, providing an explanation for the relationship between GAS5 expression and breast cancer patient prognosis. Clinically, this relationship may be circumvented by the use of GAS5-independent drugs such as imatinib, or by restoration of GAS5 expression. The latter may be achieved by the use of a dual PI3K/mTOR inhibitor, to improve apoptotic responses to conventional chemotherapies.

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Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs

Cited by 276 publications

References 60 publications

Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing

Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing

Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer

Regulation of apoptosis by long non-coding RNA GAS5 in breast cancer cells: implications for chemotherapy

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