About the Lab

We study the molecular basis of nucleic acid regulatory processes, RNAi and DNA replication in particular. We use the tools of structural biology, biochemistry and biophysics to study proteins and protein complexes associated with these processes to elucidate how they work. X-ray crystallography, EM, and other structural techniques enables us to obtain the three-dimensional structures of these molecular machines. Biochemistry, biophysics and molecular biology allow us to study properties that can be correlated to their function and biology.

The introduction of exogenous double-stranded RNA (dsRNA) into a cell can trigger the gene silencing process called RNA interference or RNAi. Although there has been remarkable progress in unraveling the components of the RNAi machinery, in order to get a complete understanding of these mechanisms we must determine how they work at the molecular level. Therefore, we embarked on structural and biochemical studies of these proteins. By solving the structure of a full-length Argonaute protein, the key component in the RNAi machinery, we identified Argonaute as “Slicer”, the effector enzyme that harbors the small RNAs, e.g. miRNAs and siRNAs, and cleaves the mRNA as directed by the siRNA. These studies enhance not only our understanding of this important pathway, but should also improve the practical use of the RNAi technology as an experimental tool for gene knockdown technology.

Another area of research in the lab is DNA replication. The goal is to understand the molecular motors involved in replication initiation.  We have been studying the viral replicative helicase E1 from papillomavirus as a model system to study helicase function and assembly as well as DNA melting and unwinding. We have also been examining the eukaryotic machinery with the Origin Recognition Complex (ORC) as the centerpiece of these studies.

What’s new in the Joshua-Tor lab?

Graduate student Katie Meze successfully defended her thesis in July.

Congratulations Dr. Meze!

recent publications

SARS-CoV-2 neutralizing antibody responses are more robust in patients with severe disease

Wang P, Liu L, Nair MS, Yin MT, Luo Y, Wang Q, Yuan T, Mori K, Solis AG, Yamashita M, Garg A, Purpura LJ, Laracy JC, Yu J, Joshua-Tor L, Sodroski J, Huang Y, Ho DD. SARS-CoV-2 neutralizing antibody responses are more robust in patients with severe disease. Emerg Microbes Infect. 2020 Dec;9(1):2091-2093. doi: 10.1080/22221751.2020.1823890. PMID: 32930052; PMCID: PMC7534308.

Evolution of DNA replication origin specification and gene silencing mechanisms

Hu Y, Tareen A, Sheu YJ, Ireland WT, Speck C, Li H, Joshua-Tor L, Kinney JB, Stillman B. Evolution of DNA replication origin specification and gene silencing mechanisms. Nat Commun. 2020 Oct 14;11(1):5175. doi: 10.1038/s41467-020-18964-x. PMID: 33056978; PMCID: PMC7560902.

The dynamic nature of the human origin recognition complex revealed through five cryoEM structures

Jaremko MJ, On KF, Thomas DR, Stillman B, Joshua-Tor L. The dynamic nature of the human origin recognition complex revealed through five cryoEM structures. Elife. 2020 Aug 18;9:e58622. doi: 10.7554/eLife.58622. PMID: 32808929; PMCID: PMC7467728.

Asterix/Gtsf1 links tRNAs and piRNA silencing of retrotransposons

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Ipsaro JJ, O’Brien PA, Bhattacharya S, Palmer AG 3rd, Joshua-Tor L. Asterix/Gtsf1 links tRNAs and piRNA silencing of retrotransposons. Cell Rep. 2021 Mar 30;34(13):108914. doi: 10.1016/j.celrep.2021.108914. PMID: 33789107; PMCID: PMC8283736.

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