The research of our laboratory is focused on the development of advanced high-resolution and single-molecule microscopy techniques and their application to study how biomolecular motors work and generate biological motion. In particular, the Gennerich Lab combines single-molecule biophysics with molecular biology and biochemistry to study the molecular mechanisms underlying cell division, intracellular organelle and mRNA transport, as well as the molecular mechanisms underlying the regulation of transcription elongation by RNA polymerases. Current research is focused on the molecular functions of the microtubule motors kinesins and cytoplasmic dynein (molecular machines that harness the chemical energy of ATP hydrolysis to perform mechanical work in eukaryotic cells), the regulation of RNA polymerase II-based transcription elongation through nucleosomes, and the molecular mechanism of transcription elongation by RNA polymerase III. We use a multidisciplinary approach integrating ultrasensitive single-molecule assays (high-resolution optical trapping and single-molecule fluorescence microscopy) and genetic approaches such as homologous recombination to dissect the mechanisms of microtubule- and DNA-based motor proteins. Our long-term goal is to understand the fundamental design principles of biomolecular motors and the molecular basis of human diseases with underlying defects in motor function.

Benoit, M. P. M. H.*, L. Rao*, A. B. Asenjo, A. Gennerich^#, and H. Sosa^#. Cryo-EM Unveils Kinesin KIF1A Processivity Mechanism and the Impact of its Pathogenic Variant P305L. Nat. Commun. 15:5530 (*: co-first authors; #: corresponding authors).

Rao, L. and A. Gennerich. Structure and Function of Dynein's Non-Catalytic Subunits. 2024. Cells, 13:330.

Liu, X., L. Rao, and A. Gennerich. Measurements of the Force-Dependent Detachment Rates of Cytoplasmic Dynein from Microtubules. 2023. “Dynein”. Methods Mol. Biol., 2623:221-238.

Rao, L., and A. Gennerich. Single-molecule studies on the motion and force generation of the Kinesin-3 motor KIF1A. 2022. “Optical Tweezers II”. Methods Mol. Biol. 2478:585-608. 

Fu, X*^,#, L. Rao*, P. Li, X. Liu, Q. Wang, A. I. Son, A. Gennerich#, J. S.-H. Liu#. Doublecortin and JIP3 are neural-specific counteracting regulators of dynein-mediated retrograde trafficking. 2022. eLife, e82218 (*: co-first authors; #: corresponding authors).

Pant, D.C.*, J. Parameswaran*, L. Rao L, L. Shi, G. Chilukuri, Z. McEachin, G. Bassell, S. Atienzar-Saez, B. Traynor, J. Glass, A. Gennerich, J. Jiang. ALS-linked KIF5A Δexon27 mutant causes neuronal toxicity through gain of function. 2022. EMBO Rep., e54234 (*: co-first authors). 

Impastato, A.C.*, A. Shemet*, N. Vepřek, G. Saper, L. Rao, H. Hess, A. Gennerich#, D. Trauner#. Optical control of mitosis with photoswitchable Eg5 inhibitor. 2022. Angew. Chem. Int. Ed., 61:e202115846 (*: co-first authors; #: corresponding authors).

Blasius, L. T.*, Y. Yue*, R. Prasad, X. Liu, A. Gennerich, and K. J. Verhey. Separate sequences in the stalk domain regulate autoinhibition and ciliary tip localization of the immotile kinesin-4 KIF7. 2021. J. Cell Sci., accepted (*: co-first authors).

Lam, A. J., L. Rao, Y. Anazawa, K. Okada, K. Chiba, S. Niwa, A. Gennerich*, D. W. Nowakowski*, R. J. McKenney*. Human Disease Mutation Within a Conserved 3₁₀-Helix in the KIF1A Motor Domain Reveals a Critical Role for Kinesin Function. 2021. Sci. Adv. 7:eabf1002 (*: corresponding authors).

Boyle, L., L. Rao, S. Kaur, X. Fan, C. Mebane, L. Hamm, A. Thornton, J. T. Ahrendsen, M. P. Anderson, J. Christodoulou, A. Gennerich, Y. Shen, W. K. Chung. Genotype and Defects in Microtubule-Based Motility Correlate with Clinical Severity in KIF1A Associated Neurological Disorder. 2021. Human Genetics and Genomics Advances 100026.

Budaitis, B. G.*, S. Jariwala*, L. Rao*, Y. Yue, D. Sept#, K. J. Verhey#, A. Gennerich#. Pathogenic Mutations in the Kinesin-3 Motor KIF1A Diminish Force Generation and Movement Through Allosteric Mechanisms. 2021. J. Cell Biol. 220:e202004227 (*: co-first authors listed alphabetically; #: corresponding authors).

Liu, X., L. Rao, and A. Gennerich. The regulatory function of the AAA4 ATPase domain of cytoplasmic dynein. 2020. Nat. Commun. 11:5952.

Brenner, D., F. Berger, L. Rao, M. P. Nicholas, and A. Gennerich. Force production of human cytoplasmic dynein is limited by its processivity. 2020. Sci. Adv. 6:eaaz4295.

Rao, L., F. Berger, M. P. Nicholas, and A. Gennerich. Molecular mechanism of cytoplasmic dynein tension sensing. 2019. Nat. Commun. 10:3332.

Rao, L., M. Hülsemann, and A. Gennerich. Combining structure-function and single-molecule studies on cytoplasmic dynein. 2018. Methods Mol. Biol. 1665:53-89.

Nicholas, M. P., F. Berger, L. Rao, S. Brenner, C. Cho, and A. Gennerich. Cytoplasmic dynein regulates its attachment to microtubules via nucleotide state-switched mechanosensing at multiple AAA domains. 2015. PNAS 12:6371-6376.

Nicholas, M. P.*, P. Höök*, S. Brenner, C. Lazar, R. B. Vallee#, and A. Gennerich#. Control of cytoplasmic dynein force production and processivity by its C-terminal domain. 2015. Nat. Commun. 6:6206 (*: Co-first authors; #: co-corresponding authors).

Nicholas, M. P., L. Rao, and A. Gennerich. An improved optical tweezers assay for measuring the force generation of single kinesin molecules. 2014. Methods Mol. Biol. 1136:171-246.

Nicholas, M. P., L. Rao, and A. Gennerich. Covalent immobilization of microtubules on glass surfaces for molecular motor force measurements and other single-molecule assays. 2014. Methods Mol. Biol. 1136:137-169.

Gennerich, A. Molecular Motors: DNA Takes Control. 2014. Nat. Nanotechnol. 9:11-12 (invited News & Views article).

Rao, L.*, Romes, E. M.*, M. P. Nicholas, S. Brenner, T. Ashutosh, A. Gennerich#, and K. C. Slep#. The yeast dynein dyn2-pac11 complex is a dynein dimerization/processivity factor: structural and single molecule characterization. 2013. Mol. Biol. Cell 24:2362-2377 (*: co-first authors; #: co-corresponding authors).

Shih, S.-M., F. Kocabas, B. Engel, A. Gennerich, W. Marshall, and A. Yildiz.Single-molecule analysis of intraflagellar transport in Chlamydomonas reinhardtii. 2013. eLife 2:e00744

Gennerich, A., and S. L. Reck-Peterson. Probing the force generation and stepping behavior of cytoplasmic dynein. 2011. Methods Mol. Biol. 783:63-80.

Reck-Peterson, S. L., R. D. Vale, and A. Gennerich. “Motile Properties of Cytoplasmic Dynein”. In: “Handbook of Dynein” (Pan Stanford Publishing). 2011. Editors: Linda Amos and Keiko Hirose.

Huckaba, T., A. Gennerich, J. E. Wilhelm, A. Chishti, and R. D. Vale. Kinesin 73 is a processive motor that localizes to Rab5-containing organelles. 2011. J. Biol. Chem. 286:7457-7467.

Yildiz, A., M. Tomishige, A. Gennerich, and R. D. Vale. Intramolecular strain coordinates kinesin stepping behavior along microtubules. 2008. Cell, 134:1030-1041.

Gennerich, A., A. P. Carter, S. L. Reck-Peterson, and R. D. Vale. Force-induced bidirectional stepping of cytoplasmic dynein. 2007. Cell 131:952-965.

Imanishi, M., N. F. Endres, A. Gennerich, and R. D. Vale. Autoinhibition regulates the motility of the C. elegans intraflagellar transport motor OSM-3. 2006. J. Cell Biol. 174:931-937.

Reck-Peterson, S. L., A. Yildiz, A. P. Carter, A. Gennerich, N. Zhang, and R. D. Vale. Stepping behavior and structural requirements for cytoplasmic dynein processivity. 2006. Cell 126:335-348.

Gennerich, A. and D. Schild. Finite-particle tracking reveals sub-microscopic size changes of mitochondria during transport in mitral cell dendrites. 2006. Phys. Biol. 3:45-53.

Gennerich, A. and D. Schild. Sizing-up finite fluorescent particles with nanometer-scale precision by convolution and correlation image analysis. 2005. Eur. Biophys. J. 34:181-99.

Gennerich, A. and D. Schild. Anisotropic diffusion in mitral cell dendrites revealed by fluorescence correlation spectroscopy. 2002. Biophys. J. 83:510-522.

Peters, F., A. Gennerich, D. Czesnik, and D. Schild. Low frequency voltage clamp: recording of voltage transients at constant average command voltage. 2000. J. Neurosci. Meth. 99:129-135.

Gennerich, A. and D. Schild. Fluorescence correlation spectroscopy in small cytosolic compartments depends critically on the diffusion model used. 2000. Biophys. J. 79:3294-3306.