ATP-dependent human RISC assembly pathways

Mayuko Yoda, Tomoko Kawamata, Zain Paroo, Xuecheng Ye, Shintaro Iwasaki, Qinghua Liu, Yukihide Tomari

Research output: Contribution to journalArticlepeer-review

260 Scopus citations


The assembly of RNA-induced silencing complex (RISC) is a key process in small RNA–mediated gene silencing. In humans, small interfering RNAs (siRNAs) and microRNAs (miRNAs) are incorporated into RISCs containing the Argonaute (AGO) subfamily proteins Ago1–4. Previous studies have proposed that, unlike Drosophila melanogaster RISC assembly pathways, human RISC assembly is coupled with dicing and is independent of ATP. Here we show by careful reexamination that, in humans, RISC assembly and dicing are uncoupled, and ATP greatly facilitates RISC loading of small-RNA duplexes. Moreover, all four human AGO proteins show remarkably similar structural preferences for small-RNA duplexes: central mismatches promote RISC loading, and seed or 3′-mid (guide position 12–15) mismatches facilitate unwinding. All these features of human AGO proteins are highly reminiscent of fly Ago1 but not fly Ago2.

Original languageEnglish (US)
Pages (from-to)17-24
Number of pages8
JournalNature Structural and Molecular Biology
Issue number1
StatePublished - Jan 2010

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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