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Dual Function of C/D Box Small Nucleolar Rnas in Rrna PNAS PLUS Modification and Alternative Pre-Mrna Splicing

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Dual Function of C/D Box Small Nucleolar Rnas in Rrna PNAS PLUS Modification and Alternative Pre-Mrna Splicing Dual function of C/D box small nucleolar RNAs in rRNA PNAS PLUS modification and alternative pre-mRNA splicing Marina Falaleevaa, Amadis Pagesb, Zaneta Matuszeka, Sana Hidmic, Lily Agranat-Tamirc, Konstantin Korotkova, Yuval Nevod, Eduardo Eyrasb,e, Ruth Sperlingc, and Stefan Stamma,1 aDepartment of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536; bDepartment of Experimental and Health Sciences, Universitat Pompeu Fabra, E08003 Barcelona, Spain; cDepartment of Genetics, Hebrew University of Jerusalem, 91904 Jerusalem, Israel; dDepartment of Microbiology and Molecular Genetics, Computation Center at the Hebrew University and Hadassah Medical Center, 91904 Jerusalem, Israel; and eCatalan Institution for Research and Advanced Studies, E08010 Barcelona, Spain Edited by James E. Dahlberg, University of Wisconsin Medical School, Madison, WI, and approved February 5, 2016 (received for review October 1, 2015) C/D box small nucleolar RNAs (SNORDs) are small noncoding RNAs, SNORD fragments are not microRNAs, which have an average and their best-understood function is to target the methyltrans- length of 21–22 nt (13–16), and suggests that these fragments may ferase fibrillarin to rRNA (for example, SNORD27 performs 2′-O- have additional functions. methylation of A27 in 18S rRNA). Unexpectedly, we found a subset The association of some SNORDs with specific diseases sug- of SNORDs, including SNORD27, in soluble nuclear extract made gests that they may possess functions in addition to directing the under native conditions, where fibrillarin was not detected, indi- 2′-O-methylation of rRNA. For example, the loss of SNORD116 cating that a fraction of the SNORD27 RNA likely forms a protein expression is a decisive factor in Prader–Willi syndrome, the most complex different from canonical snoRNAs found in the insoluble common genetic cause for hyperphagia and obesity (17, 18). nuclear fraction. As part of this previously unidentified complex, SNORD60 is involved in intracellular cholesterol trafficking, which SNORD27 regulates the alternative splicing of the transcription is independent of its suggested function in rRNA methylation factor E2F7 pre-mRNA through direct RNA–RNA interaction without (19), and SNORDs U32a, U33,andU35a mediate lipotoxic stress, methylating the RNA, likely by competing with U1 small nuclear ri- possibly through their cytosolic function (20). Although SNORDs bonucleoprotein (snRNP). Furthermore, knockdown of SNORD27 acti- are considered housekeeping genes, the expression of some vates previously “silent” exons in several other genes through base SNORDs is altered in cancer. For example, changes in the expression complementarity across the entire SNORD27 sequence, not just the of SNORD27, -30, -25,and-31 mark the progression of smoldering antisense boxes. Thus, some SNORDs likely function in both rRNA and multiple myeloma (21), and SNORD50 deletions are associated with pre-mRNA processing, which increases the repertoire of splicing reg- prostate and breast cancer (22–24). Genome-wide comparison of ulators and links both processes. SNORD expression between cancer and normal cells showed the presence of two classes of SNORDs that differ in their terminal alternative splicing | gene regulation | snoRNAs | pre-mRNA processing stems but are made from the same SNORD hosting intron (25). Studies in yeast have shown that cellular nutritional status can mall nucleolar RNAs (snoRNAs) are 60- to 300-nt-long control the formation of SNORDs. A complex of four proteins BIOCHEMISTRY Snoncoding RNAs that accumulate in the nucleolus. Based on [Rvb1, Rvb2, Tah1, and Phi1 (R2TP)] stabilizes NOP58 under conserved sequence elements, snoRNAs are classified as C/D box conditions of growth. Under starving conditions, the R2TP com- small nucleolar RNAs (SNORDs) or H/ACA box snoRNAs plex localizes to the cytosol, destabilizing NOP58 formation and (SNORAs). SNORDs contain sequence elements termed C inhibiting small nucleolar ribonucleoprotein (snoRNP) formation (RUGAUGA) and D (CUGA) boxes, usually present in duplicates (26, 27), suggesting that there is a cell program that regulates (C′ and D′ boxes), and up to two antisense boxes that hybridize to snoRNP composition. the target RNA (1). In humans, SNORDs are usually derived from introns. After the splicing reaction,intronsareexcisedaslariats, Significance which are then opened by the debranching enzyme and sub- sequently degraded. Intronic SNORDs escape this degradation by C/D box small nucleolar RNAs (SNORDs) are abundant, short, forming a protein complex that consists of non-histone chromosome nucleoli-residing, noncoding RNAs that guide the methyl- protein 2-like 1 (NHP2L1, 15.5K, SNU13), nucleolar protein 5A transferase fibrillarin to perform 2′-O-methylation of target (NOP56), nucleolar protein 5 (NOP58), and fibrillarin (2–4). The RNAs. We identified 29 SNORDs present in a fibrillarin-con- SNORD protein complex forms through the entry of the snoRNA taining fraction as well as a fibrillarin-free fraction enriched in and fibrillarin to a complex containing NHP2L1, NOP58, and at spliceosomes. One of these SNORDs, SNORD27, directs rRNA leastfiveassemblyfactors(5).TheSNORDactsasascaffoldforthe methylation and regulates alternative pre-mRNA splicing (AS) final protein complex formation and also controls recognition of of E2F7 pre-mRNA, a transcriptional repressor of cell cycle- SNORD27 E2F7 other RNAs using the antisense boxes. The antisense boxes recog- regulated genes. likely regulates pre-mRNA AS nize sequences in rRNA, resulting in the fifth nucleotide upstream by masking splice sites through base pairing. This previously of the D or D′ box being 2′-O-methylated by fibrillarin (1). Struc- unidentified function of SNORDs increases the number of fac- tural studies indicate that the active form of SNORDs is dimeric (6). tors regulating AS, a critical step in the expression of the vast The conserved overall structure of SNORDs allows the identifi- majority of human genes, and highlights a potential coupling cation of their putative target RNA binding sites. However, numer- between AS, cell cycle, proliferation, and ribosome biogenesis. ous SNORDs without obvious target RNAs have been identified – “ ” Author contributions: M.F., E.E., R.S., and S.S. designed research; M.F., A.P., Z.M., S.H., L.A.-T., (7 10) and are termed orphan snoRNAs. Genome-wide deep Y.N., and E.E. performed research; K.K. contributed new reagents/analytic tools; M.F., R.S., sequencing experiments identified shorter but stable SNORD and S.S. analyzed data; and M.F., R.S., and S.S. wrote the paper. fragments that were found in all species tested, ranging from The authors declare no conflict of interest. mammals to the protozoan Giardia lamblia (11) and Epstein– This article is a PNAS Direct Submission. Barr virus (12). Fragments longer than 27 nt generated by 1To whom correspondence should be addressed. Email: [email protected]. SNORDs will likely not bind argonaute proteins that bind to 21- to This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 22-nt-long microRNAs. These differences in size indicate that most 1073/pnas.1519292113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1519292113 PNAS | Published online March 8, 2016 | E1625–E1634 Downloaded by guest on October 2, 2021 Taken together, these findings suggest that cells modify SNORDs ceptor 2C pre-mRNA (31), and SNORD88C regulates alternative expression, that SNORDs are structurally more diverse than pre- splicing of FGFR3 pre-mRNA (32). Although proof of principle viously recognized, and that SNORDs have additional cellular experiments have shown that methylation of the branch point functions other than 2′-O-methylation of rRNAs. adenosine by engineered snoRNAs can change alternative splicing A previously described noncanonical function of SNORDs is (33–35), the mechanism by which SNORDs regulate splice site their influence on alternative exon selection. Alternative pre- selection in vivo is not clear. mRNA splicing is a mechanism that controls the inclusion of Here, we used a native isolation procedure to characterize exons and the retention of introns in mature mRNA. More than SNORDs from the nucleoplasma (36, 37) that were soluble under 94% of human genes are estimated to undergo alternative splicing physiological salt extraction conditions. These SNORDs were found (28, 29), which greatly increases the complexity of the tran- in complexes with splicing factors, where fibrillarin was not detected. scriptome (30). For example, the neuron-specific SNORD115 We characterized the cancer-relevant SNORD27 in detail and promotes the inclusion of an alternative exon in the serotonin re- found that it regulates alternative splicing of the E2F7 transcription A Dounce homogenization C SNORD27 AS probe of HeLa cells in isotonic buffer 5ntSNORD27 5nt (Homogenate) Separation of nuclei from cytoplasm in glycerol cushion CCytoplasm Nuclear sup. Cytoplasm Homogenate Crude nucleiWashed nucleiNuclear pellet Washing of the Crude nuclei SNORD27 72 nt RPA Sonication of the washed nuclei Chromatin precipitation 200S 60S-70S Resuspension Nuclear of the nuclear supernatant (NS) P 45% 10% M pellet (NP) D glycerol conc. 150 in RIPA and HY 100 sonication Fractionation in 1 3 5 7 9 11 13 15 17 19 90 10-45% glycerol gradients 80 SNORD27 70 B 60 RPA 50 40 WB: Cytoplasm Nuclear sup. 30 Homogenate CrudeWashed nuclei nucleiNuclear pellet PRP8 220 kDa 20 PRPF39 78 kDa E WB: 1 3 5 7 9 11 13 15 17 19 CBP80 80 kDa CBP80
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