Ian MacRae, PhD
Professor
Department of Integrative Structural and Computational Biology
Research Focus
RNA interference (RNAi) is a broad-spread mechanism of gene silencing that plays a fundamental role in many aspects of eukaryotic biology including viral defense, developmental timing, stem cell division, memory and learning. We are interested in understanding the molecular mechanisms underlying RNA interference (RNAi) and related RNA silencing processes. Our approach is to combine techniques in structural biology with biochemistry and cell biology in order to understand the mechanistic details of RNAi.
On the molecular level RNAi is mediated by a family of ribonucleo-protein complexes called RNA-Induced Silencing Complexes (RISCs), which silence genes by mediating translational repression and degradation of targeted message RNAs. The versatility and power of RNAi arises from the fact that RISC can be programmed to target any nucleic acid sequence for silencing. RISC programming is therefore a critical cellular function, requiring the action of a specialized macromolecular assembly called the RISC-loading complex (RLC). Our current research is focused on illuminating the structure and catalytic mechanism of the RLC with the hope that this knowledge will facilitate the development of RNAi-based therapeutics for the treatment of human disease.
Molecular scissors caught in action: A structural blueprint for RNA therapeutics
A Scripps Research team has captured the first high-resolution structural images of human Argonaute 2 in its cutting-ready state, revealing why some small interfering RNA (siRNA) molecules work better than others and how to design more effective ones for this emerging therapy.
Select Publications
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Sarkar, Sucharita; MacRae, Ian J. Molecular arms in microbial defense: Argonautes and Cas4 nucleases team up. Molecular Cell 2025, 85.
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De, Dipayan; Sarkar, Sucharita; Gebert, Luca F.R.; Wiryaman, Timothy; Anzelon, Todd A.; MacRae, Ian J. A conserved PIWI silencing complex detects piRNA-target engagement. Molecular Cell 2025, 85.
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Liu, Ting Yu M.; Tibbe, Debora; Engler, Jan Broder; Hermans-Borgmeyer, Irm; Borgmeyer, Uwe; De Maruri, Kerstin Robles; Lessel, Davor; MacRae, Ian J.; Kreienkamp, Hans Jürgen Dysregulation of AGO2-miRNA dynamics underlies the AGO2-associated Lessel–Kreienkamp syndrome. Nucleic Acids Research 2025, 53.
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Zolboot, Norjin; Xiao, Yao; Du, Jessica X.; Ghanem, Marwan M.; Choi, Su Yeun; Junn, Miranda J.; Zampa, Federico; Huang, Zeyi; MacRae, Ian J.; Lippi, Giordano MicroRNA mechanisms instructing Purkinje cell specification. Neuron 2025, 113.
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Dong, Xiyu; Sheng, Kai; Gebert, Luca F.R.; Aiyer, Sriram; Macrae, Ian J.; Lyumkis, Dmitry; Williamson, James R. Assembly of the bacterial ribosome with circularly permuted rRNA. Nucleic Acids Research 2024, 52.
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Xiao, Yao; Liu, Ting Yu M.; MacRae, Ian J. A tiny loop in the Argonaute PIWI domain tunes small RNA seed strength. EMBO Reports 2023, 24.
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