Sam68 binds Alu-rich introns in SMN and promotes pre-mRNA circularization

Vittoria Pagliarini, Claudio Sette, Ariane Jolly, Pamela Bielli, Valentina Di Rosa, Pierre De la Grange

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

20 Citazioni (Scopus)

Abstract

The Spinal Muscular Atrophy (SMA) gene SMN was recently duplicated (SMN1 and SMN2) in higher primates. Furthermore, invasion of the locus by repetitive elements almost doubled its size with respect to mouse Smn, in spite of an almost identical protein-coding sequence. Herein, we found that SMN ranks among the human genes with highest density of Alus, which are evolutionary conserved in primates and often occur in inverted orientation. Inverted repeat Alus (IRAlus) negatively regulate splicing of long introns within SMN, while promoting widespread alternative circular RNA (circRNA) biogenesis. Bioinformatics analyses revealed the presence of ultra-conserved Sam68 binding sites in SMN IRAlus. Cross-link-immunoprecipitation (CLIP), mutagenesis and silencing experiments showed that Sam68 binds in proximity of intronic Alus in the SMN pre-mRNA, thus favouring circRNA biogenesis in vitro and in vivo. These findings highlight a novel layer of regulation in SMN expression, uncover the crucial impact exerted by IRAlus and reveal a role for Sam68 in SMN circRNA biogenesis.
Lingua originaleEnglish
pagine (da-a)633-645
Numero di pagine13
RivistaNucleic Acids Research
Volume48
DOI
Stato di pubblicazionePubblicato - 2020

Keywords

  • SAM68

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