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.
C.R. Faehnle*, J. Walleshauser*, and L. Joshua-Tor (2014) Mechanism of Dis3L2 substrate recognition in the Lin28/let-pathway. Nature, 514, 252-256. doi:10.1038/nature13553.
Ipsaro*, J.J., A.D. Haase*, A.D., Knott, S.R., Joshua-Tor, L.** and Hannon, G.J. **2012. The structural biochemistry of Zucchini implicates it as a nuclease in piRNA biogenesis. Nature 491: 279–283.
Elkayam, E. Kuhn, C.-D., Tocilj, A., Haase, A.D., Greene, E.M., Hannon, G.J. and Joshua-Tor, L. 2012. The structure of human Argonaute-2 in complex with miR-20a. Cell 150: 100–110.
Schalch, T., Job, G., Shanker, S., Partridge, J.F. and Joshua-Tor, L. 2012. The Chp1-Tas3 core is a multifunctional platform critical for gene silencing by RITS. Nat. Struct. Mol. Biol. 18: 1351–1357.
Enemark, E.J. and Joshua-Tor, L. 2006. Mechanism of DNA translocation in a replicative hexameric helicase. Nature 442: 270–275.
Knowing what to keep and what to trash: how an enzyme distinguishes cellular messages
August 3, 2014
Human Argonaute proteins: to slice or not to slice?
June 6, 2013
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)