RISC binds inexactly matching target RNAs

Stable Identifier
Reaction [binding]
Homo sapiens
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RISCs can bind target RNAs that do not exactly match the guide RNA carried by an Argonaute. Binding is especially dependent on base-pairing between the target RNA and the eight 5' nucleotides of the guide RNA (miRNA or siRNA). After binding, Argonaute-1 (AGO1, EIF2C1), AGO3 (EIF2C3), and AGO4 (EIF2C4) are incapable of cleavage in all cases. AGO2 is capable of cleaving the target RNA but not if mismatches exist in the middle of the guide (centered about 10 nucloetides from the 5' end of the guide RNA). In the absence of cleavage the target RNA remains bound by the RISC, which inhibits translation of the target RNA and causes the RNA to enter the decay pathway. In vivo, inhibition of translation requires interaction of AGO with a TNRC6 protein and MOV10. The phosphoinositide-3 kinase/mTOR pathway increases expression of GW182, a TNRC6 protein, which increases the portion of AGO:miRNA in high molecular weight complexes with mRNA.

Literature References
PubMed ID Title Journal Year
26140367 Human Argonaute 2 Has Diverse Reaction Pathways on Target RNAs

Hohng, S, Jung, SR, Jo, MH, Shin, S, Song, JJ, Kim, E

Mol. Cell 2015
24043833 Structural features of Argonaute-GW182 protein interactions

Aebersold, R, Niessing, D, Sattler, M, Herzog, F, Meister, G, Hennig, J, Pfaff, J

Proc. Natl. Acad. Sci. U.S.A. 2013
19383768 The C-terminal domains of human TNRC6A, TNRC6B, and TNRC6C silence bound transcripts independently of Argonaute proteins

Lazzaretti, D, Tournier, I, Izaurralde, E

RNA 2009
18461144 Systematic identification of mRNAs recruited to argonaute 2 by specific microRNAs and corresponding changes in transcript abundance

Brown, PO, Herschlag, D, Hendrickson, DG, Ferrell, JE, Hogan, DJ

PLoS One 2008
16289642 Identification of novel argonaute-associated proteins

Urlaub, H, Landthaler, M, Lührmann, R, Tuschl, T, Peters, L, Chen, PY, Meister, G

Curr Biol 2005
19470757 Functional Dissection of Human TNRC6, GW182-related, Family of proteins

Shiekhattar, R, Baillat, D

Mol Cell Biol 2009
18978028 Molecular characterization of human Argonaute-containing ribonucleoprotein complexes and their bound target mRNAs

Ojo, T, Landthaler, M, Hafner, M, Tuschl, T, Soll, SJ, Zavolan, M, Gaidatzis, D, Dinic, L, Rothballer, A, Chen, PY

RNA 2008
16284623 A role for the P-body component GW182 in microRNA function

Liu, J, Hannon, GJ, Wohlschlegel, J, Yates, JR 3rd, Rivas, FV, Parker, R

Nat Cell Biol 2005
17632058 Molecular basis for target RNA recognition and cleavage by human RISC

Schroeder, R, Ameres, SL, Martinez, J

Cell 2007
28781232 Multivalent Recruitment of Human Argonaute by GW182

Li, H, Elkayam, E, Faehnle, CR, Morales, M, Sun, J, Joshua-Tor, L

Mol. Cell 2017
25359968 Structural basis for microRNA targeting

Sheu-Gruttadauria, J, Schirle, NT, MacRae, IJ

Science 2014
25568082 In vivo, Argonaute-bound microRNAs exist predominantly in a reservoir of low molecular weight complexes not associated with mRNA

Vidigal, JA, Ventura, A, Briskin, D, Leslie, CS, DeMatteo, RG, Lindsten, T, Thompson, CB, La Rocca, G, Radler, MR, Olejniczak, SH, González, AJ, Tuschl, T, Spraggon, L

Proc. Natl. Acad. Sci. U.S.A. 2015
19398495 Mammalian GW182 contains multiple Argonaute-binding sites and functions in microRNA-mediated translational repression

Wakiyama, M, Takimoto, K, Yokoyama, S

RNA 2009
17128271 Evidence that microRNAs are associated with translating messenger RNAs in human cells

Nilsen, TW, Fisher, J, Maroney, PA, Yu, Y

Nat Struct Mol Biol 2006
15014042 Specificity of microRNA target selection in translational repression

Sharp, PA, Doench, JG

Genes Dev 2004
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