Jeff Gelles, Ph.D.
Brandeis University, Aron and Imre Tauber Professor
of Biochemistry and Molecular Pharmacology Motor Enzymes: Single-molecule Biochemistry
B.A., Harvard University
Ph.D., California Institute of Technology
Little Engine Shop
Living cells are chock full of dynamic complexes of protein, RNA, and DNA molecules. We want to understand the fundamental chemical and physical mechanisms through which these molecular machines perform essential biological processes. Our research is focused in two different areas of study: 1) the function of the molecular machines essential to gene expression and its regulation, in particular those that control the synthesis and processing of messenger RNAs, and 2) the function of molecular machines essential to the organization and utilization of the actin and microtubule cytoskeleton of eukaryotic cells.
All of the processes that we study involve dynamic molecular assemblies and multiple reaction intermediates. It is challenging to study their mechanisms using conventional biochemical approaches because different individual molecules in a population are doing different things at the same time. To overcome this “crowd noise problem”, we have developed and used single-molecule light microscopy methods that allow us to observe the behavior of isolated individual molecules and molecular complexes in real time. Using these techniques we can directly observe the assembly, rearrangements, and disassembly of molecular complexes, characterize conformational changes, and detect biochemical reactions. Together, these methods permit comprehensive investigation of molecular mechanisms, revealing reaction pathways and allowing quantitative evaluation and modeling of reaction dynamics. We perform these single-molecule experiments both in systems reconstituted from purified componentsand in extracts that recapitulate the molecular complexity of the living cell.
Our research uses approaches from scientific fields ranging from cell biology and genetics through biochemistry and molecular biology to physical chemistry and condensed-matter physics. In our experience, the most exciting advances in science often arise when scientists from different disciplines collaborate.
Selected recent publications from
- Friedman, L.J. & Gelles, J. “Multi-wavelength single-molecule fluorescence analysis of transcription mechanisms.” Methods (2015). doi:10.1016/j.ymeth.2015.05.026
- Jansen, S. et al. Single-molecule imaging of a three-component ordered actin disassembly mechanism. Nat Commun 6, (2015). doi:10.1038/ncomms8202
- Ticau, S., Friedman, L.J., Ivica, N.A., Gelles, J. & Bell, S.P. Single-Molecule Studies of Origin Licensing Reveal Mechanisms Ensuring Bidirectional Helicase Loading. Cell 161, 1–13 (2015). doi:10.1016/j.cell.2015.03.012
- Wang TY, Friedman LJ, Gelles J, Min W, Hoskins AA, Cornish VW. The covalent trimethoprim chemical tag facilitates single molecule imaging with organic fluorophores. Biophys J. 2014 Jan 7;106(1):272-8. PubMed PMID: 24411259; PubMed Central PMCID: PMC3907213.
- Smith BA, Gelles J, Goode BL. Single-molecule studies of actin assembly and disassembly factors. Methods Enzymol. 2014;540:95-117.
- Shcherbakova I, Hoskins AA, Friedman LJ, Serebrov V, Corrêa IR Jr, Xu MQ, Gelles J, Moore MJ. Alternative spliceosome assembly pathways revealed by single-molecule fluorescence microscopy. Cell Rep. 2013 Oct 17;5(1):151-65. PubMed PMID: 24075986; PubMed Central PMCID: PMC3927372.
- Smith BA, Padrick SB, Doolittle LK, Daugherty-Clarke K, Corrêa IR Jr, Xu MQ, Goode BL, Rosen MK, Gelles J. Three-color single molecule imaging shows WASP detachment from Arp2/3 complex triggers actin filament branch formation. Elife. 2013 Sep 3;2:e01008. PubMed PMID: 24015360; PubMed Central PMCID: PMC3762362.
- RNA polymerase approaches its promoter without long-range sliding along DNA. Friedman LJ, Mumm JP, Gelles J. Proc Natl Acad Sci U S A. 2013 May 29. PMID: 23720315.
- Single-molecule colocalization FRET evidence that spliceosome activation precedes stable approach of 5' splice site and branch site. Crawford, D.J., Hoskins, A.A., Friedman, L.J., Gelles, J. & Crawford, D.J., Hoskins, A.A., Friedman, L.J., Gelles, J. & Moore, M.J. PNAS (2013). doi:10.1073/pnas.1219305110.
- Pathway of actin filament branch formation by Arp2/3 complex revealed by single-molecule imaging. Smith BA, Daugherty-Clarke K, Goode BL, Gelles J. Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1285-90. doi: 10.1073/pnas.1211164110. Epub 2013 Jan 4.
- Operator sequence alters gene expression independently of transcription factor occupancy in bacteria. Garcia HG, Sanchez A, Boedicker JQ, Osborne M, Gelles J, Kondev J, Phillips R. Cell Rep. 2012 Jul 26;2(1):150-61. doi: 10.1016/j.celrep.2012.06.004.
- Rocket launcher mechanism of collaborative actin assembly defined by single-molecule imaging. Breitsprecher D, Jaiswal R, Bombardier JP, Gould CJ, Gelles J, Goode BL. Science. 2012 Jun 1;336(6085):1164-8. doi: 10.1126/science.1218062.
- Mechanism of transcription initiation at an activator-dependent promoter defined by single-molecule observation. Friedman LJ, Gelles J. Cell. 2012 Feb 17;148(4):679-89. doi: 10.1016/j.cell.2012.01.018.
- New insights into the spliceosome by single molecule fluorescence microscopy. Hoskins AA, Gelles J, Moore MJ. Curr Opin Chem Biol. 2011 Dec;15(6):864-70. doi: 10.1016/j.cbpa.2011.10.010. Review.
- Mechanism of transcriptional repression at a bacterial promoter by analysis of single molecules. Sanchez A, Osborne ML, Friedman LJ, Kondev J, Gelles J. EMBO J. 2011 Aug 9;30(19):3940-6. doi: 10.1038/emboj.2011.273.
- Ordered and dynamic assembly of single spliceosomes. Hoskins AA, Friedman LJ, Gallagher SS, Crawford DJ, Anderson EG, Wombacher R, Ramirez N, Cornish VW, Gelles J, Moore MJ. Science. 2011 Mar 11;331(6022):1289-95. doi: 10.1126/science.1198830.
View Complete Publication List on PubMed: Jeff
Last review: June 2, 2015.