Professor & HHMI Investigator
Ph.D., The Weizmann Institute of Science, 1991
Our cells depend on thousands of proteins and nucleic acids that function as tiny machines: molecules that build, fold, cut, destroy, and transport all of the molecules essential for life. My group is discovering how these molecular machines work, looking at interactions between individual atoms to understand how they activate gene expression, DNA replication, and small RNA biology.
In Leemor Joshua-Tor’s lab, researchers study the molecular basis of nucleic acid regulatory processes using the tools of structural biology and biochemistry. One such regulatory process is RNA interference (RNAi), in which a small double-stranded RNA triggers gene silencing. Joshua-Tor and her team offered critical insight when they solved the crystal structure of the Argonaute protein and identified it as the long-sought Slicer. They then went on to explore the mechanism of the slicing event. The structure of human Argonaute 2 (hAgo2) bound to a microRNA (miRNA) guide allowed Joshua-Tor and her colleagues to understand how mRNA is cleaved during RNAi. This year, members of the Joshua-Tor lab explored the function of a very similar protein, called Argonaute 1, that has no slicing ability, even though it is almost identical in structure to the slicing hAgo2. Using biochemical methods and mutational analysis, they were able to identify key parts of the protein that are required for slicing activity. The lab also studies the generation of PIWI-interacting RNAs (piRNAs), which serve to protect the genome of germ cells. With colleagues in the Hannon lab, Joshua-Tor’s team also determined the structure and function of Zucchini, a key nuclease in the initial generation of piRNAs in fruit flies. In other work, the lab is exploring the mechanisms of heterochromatin formation and gene silencing through the study of a protein complex called RNA-induced initiation of transcriptional gene silencing (RITS). Joshua-Tor is also well known for her work on the E1 helicase enzyme, which acts to unwind DNA strands during the DNA replication process.
Naguib, Adam and Bencze, Gyula and Cho, Hyejin and Zheng, Wu and Tocilj, Ante and Elkayam, Elad and Faehnle, Christopher R and Jaber, Nadia and Pratt, Christopher P and Chen, Muhan and Zong, Wei-Xing and Marks, Michael S and Joshua-Tor, Leemor and Pappin, Darryl J and Trotman, Lloyd C (2015) PTEN Functions by Recruitment to Cytoplasmic Vesicles. Molecular Cell 58(2) pp. 255-268.
Kuhn, C. D. and Wilusz, J. E. and Zheng, Y. and Beal, P. A. and Joshua-Tor, L. (2015) On-Enzyme Refolding Permits Small RNA and tRNA Surveillance by the CCA-Adding Enzyme. Cell 160(4) pp. 644-658.
Ipsaro, J. J. and Joshua-Tor, L. (2015) From guide to target: molecular insights into eukaryotic RNA-interference machinery. Nat Struct Mol Biol 22(1) pp. 20-28.
Faehnle, C. R. and Walleshauser, J. and Joshua-Tor, L. (2014) Mechanism of Dis3l2 substrate recognition in the Lin28-let-7 pathway. Nature 514(7521) pp. 252-6.
Lee, S. J. and Syed, S. and Enemark, E. J. and Schuck, S. and Stenlund, A. and Ha, T. and Joshua-Tor, L. (2014) Dynamic look at DNA unwinding by a replicative helicase. Proceedings of the National Academy of Sciences of the United States of America 111(9) pp. E827-35.Additional materials of the author at
CSHL Institutional Repository
Biologists characterize enzymatic identity of key player in generating genome-protecting piRNAs
CSHL researchers solve structure of human protein critical for silencing genes
CSHL team solves a protein complex’s molecular structure to explain its role in gene silencing
2014 ACE Women's Network, New York, Women in Science and Education Leadership Award
Fellow of the American Association for the Advancement of Science (AAAS)