SNORD80-guided 2'-O-methylation stabilizes the lncRNA GAS5 to regulate cellular stress responses

<p dir="ltr">The long noncoding RNA (lncRNA) growth arrest-specific 5 (GAS5) plays an important role in regulating cellular responses to stress and is involved in the pathogenesis of a variety of diseases. Intriguingly, the GAS5 gene harbors up to 10 antisense C/D box small nucleolar RNAs (snoRNAs) within its introns. The canonical function of C/D box snoRNAs is to guide the 2'-O-methylation of ribosomal RNAs (rRNAs), essential for ribosome biogenesis. Nevertheless, we have found that one of the GAS5-hosted C/D box snoRNAs, SNORD80, is upregulated, along with GAS5, in cells undergoing metabolic stress. Here, we show that SNORD80 stabilizes GAS5 by guiding its 2'-O-methylation via the rRNA 2'-O-methyltransferase fibrillarin (FBL), thereby playing a role in GAS5-mediated cellular stress responses. These results uncover a novel mechanism through which SNORD80 controls the expression of GAS5 in cis through 2'-O-methylation, with practical implications of manipulating the SNORD80-GAS5 axis as a potential avenue for disease treatment. Moreover, the results broaden the functional scope of C/D box snoRNAs and point out the potential importance of 2'-O-methylation in regulating the expression of lncRNAs.</p>