Dual Function of C/D Box Small Nucleolar RNAs in rRNA Modification and Alternative Pre-mRNA Splicing


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′-O-methylation 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.

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Published in Proceedings of the National Academy of Sciences of the United States of America, v. 113, no. 12, p. E1625-E1634.

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We thank the University of Kentucky Proteomics Core, which was supported by National Institute of General Medical Sciences Centers of Biomedical Research Excellence Grant P20GM103486-09 and the Office of the Vice President for Research of the University of Kentucky as well as High-End Instrumentation Grant S10RR029127. This work was supported by Postdoctoral Fellowship 13POST16820024 from the American Heart Association (to M.F.); MINECO (Ministerio de Economía y Competitividad) Spanish Government Grant BIO2014-52566-R (to A.P. and E.E.); Consolider RNAREG Grant CSD2009-00080 (to A.P. and E.E.); Sandra Ibarra Foundation for Cancer Grant FSI2013 (to A.P. and E.E.); AGAUR (Agència de Gestió d’Ajuts Universitaris i de Recerca) Grant 2014-SGR1121 (to A.P. and E.E.); USA-Israel Binational Science Foundation, Transformative Grant 2010508 (to R.S. and S.S.); NIH Grants 01GM079549 (to R.S.) and 01GM083187 (to S.S.); and the Foundation for Prader-Willi Research (S.S.).