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.

Box H/ACA family snoRNAs share hallmark secondary structure called "hairpin-hinge-hairpin-tail" that includes two hairpin domains linked with a single-stranded region (hinge) and 3 -terminus region (tail) [2] . Boxes H and ACA are located in a close vicinity of the hairpin in the hinge and tail regions, respectively (Figure 1(b) ). Box H represents a conserved ANANNA (N stands for any nucleotide) motif, while box ACA is a trinucleotide located 3 nt before the 3 -terminus. Each hairpin consists of internal and external loops. A 9-13-nt-long guide sequence is located on both strands of the inner loop. During interaction with the target RNA molecule the complementary sequences of box H/ACA Figure 1 : (a) Box C/D snoRNAs share two conserved elements: boxes b (PuUGAUGA) and D (CUGA) located at the 5 -and 3 -termini of the RNA molecule, respectively. Often, box C/D snoRNAs also have an additional copy of internally located C or D boxes. A complex of box C/D snoRNA with nucleolar proteins Nop1p (fibrillarin), Nop56p, Nop58p, and Snu13p (15.5 kDa) catalyzes site-specific 2 -O-methylation of the nucleotide in target RNA. S-Adenosylmethionine (SAM) serves as the donor of the methyl group and is converted to S-adenosylhomocysteine (SAH). (b) Box H/ACA snoRNAs have "hairpin-hinge-hairpin-tail" structure with boxes H (ANANNA) and ACA located within the singlestranded (hinge) and 3 -terminus (tail) regions, respectively. Pseudouridylation complex includes dyskerin (the pseudouridine synthase), GAR1, NHP2, and NOP10 proteins. Box H/ACA snoRNP catalyzes site-specific isomerization of uridine (U) to pseudouridine (Ψ) in target RNA. *SnoRNA with target RNA in square brackets designates snoRNP enzyme-substrate complex. RNA flank two nucleotides including a uridine residue, which is further subjected to U/Ψ isomerization. Thus, the threedimensional structure of the conserved motif enables the access of pseudouridylation enzymes to the substrate uridine. The distance between the target nucleotide and H/ACA box in rRNA-snoRNA duplex is 14-15 nt long [2, 8] .