Asymmetry in the assembly of the RNAi enzyme complex.
A key step in RNA interference (RNAi) is assembly of the RISC, the protein-siRNA complex that mediates target RNA cleavage. Here, we show that the two strands of an siRNA duplex are not equally eligible for assembly into RISC. Rather, both the absolute and relative stabilities of the base pairs at the 5' ends of the two siRNA strands determine the degree to which each strand participates in the RNAi pathway. siRNA duplexes can be functionally asymmetric, with only one of the two strands able to trigger RNAi. Asymmetry is the hallmark of a related class of small, single-stranded, noncoding RNAs, microRNAs (miRNAs). We suggest that single-stranded miRNAs are initially generated as siRNA-like duplexes whose structures predestine one strand to enter the RISC and the other strand to be destroyed. Thus, the common step of RISC assembly is an unexpected source of asymmetry for both siRNA function and miRNA biogenesis.
Schwarz
Dianne S
DS
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Lazare Research Building, 364 Plantation Street, Worcester, MA 01605, USA.
Hutvágner
György
G
Du
Tingting
T
Xu
Zuoshang
Z
Aronin
Neil
N
Zamore
Phillip D
PD
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020137:Base Pair Mismatch; D020029:Base Pairing; D001483:Base Sequence; D004331:Drosophila melanogaster / Q000196:embryology; D006860:Hydrogen Bonding; D007700:Kinetics; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D020365:RNA Helicases / Q000378:metabolism; D034622:RNA Interference; D016372:RNA, Antisense / Q000737:chemistry / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000378:metabolism*; D022661:RNA, Untranslated / Q000737:chemistry / Q000378:metabolism*; D034743:RNA-Induced Silencing Complex / Q000737:chemistry / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D035683:MicroRNAs; D016372:RNA, Antisense; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; D034743:RNA-Induced Silencing Complex; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020365:RNA Helicases