Regulatory Role of Small Nucleolar RNAs in Human Diseases

Stepanov, Grigory A.; Filippova, Julia A.; Komissarov, Andrey B.; Kuligina, Elena V.; Richter, Vladimir A.; Semenov, Dmitry V.

Changes in the level of snoRNAs circulating in body fluids were shown to be induced by different stress factors. At the scale of the whole organism any trauma is considered to be stress causing shift in homeostasis. Two box C/D snoRNAs U48 and U38 were found to be significantly overexpressed in serum of patients with anterior cruciate ligament (ACL) injury [91] . Moreover, U38 snoRNA expression level was reliably elevated in patients with cartilage damage associated with ACL injury. The snoRNA U38 may therefore serve as a biomarker for early diagnostics of osteoarthritis following joint injury. Changes of snoRNA level can also occur in mammalian cells exposed to chemical stress factors. It has been demonstrated that Chinese hamster ovary (CHO) cells contain increased level of three box C/D snoRNAs-U32a, U33 and U35a, when exposed to fatty acids [92] . These snoRNAs are encoded within different introns of the ribosomal protein L13a (RPL13a). Under such conditions box C/D snoRNAs accumulate in cytoplasm, but not nuclei, thus suggesting a new cytoplasmic function of small nucleolar RNAs. Fatty acids are known to be toxic to mammalian cells. Lipotoxicity is characterized by initiation of oxidative stress, endoplasmic reticulum (ER) dysfunction, and can further lead to proinflammatory processes and apoptotic cell death [93, 94] . First it has been demonstrated that RPL13a is largely involved in activation of palmitate-induced cell death. Saturated fatty acids (myristate, palmitate, and stearate), unlike less toxic, unsaturated fatty acids (palmitoleate and oleate), have been reported to induce U32a, U33, and U35a snoRNA overexpression [92] . Despite the upregulation of snoRNA, there was no detectable change in 2 -O-methylation level of rRNAs. Specific downregulation of the reported box C/D RNAs protected cells from lipotoxicity. It is also notable that the suppression of U32a, U33, and U35a box C/D RNA genes in cells resulted in inhibited accumulation of H 2 O 2 -derived reactive oxygen species, thus implicating the participation of these snoRNAs in a common mechanism of cellular response to oxidative stress. In vivo experiments showed that administration of lipopolysaccharides induces U32a, U33, and U35a snoRNA expression in mouse liver [92] . Thus, small nucleolar RNAs are capable of participating in the regulation of cellular response to external stress and controlling activation of apoptosis.