Berl R Oakley


Berl R. Oakley
  • Irving S. Johnson Distinguished Professor of Molecular Biology

Research

My lab discovered γ-tubulin and helped to uncover its role in microtubule nucleation. More recent work in my lab with γ-tubulin mutants of the filamentous fungus Aspergillus nidulans has revealed that γ-tubulin has important but poorly understood functions in cell cycle regulation independent of its role in microtubule nucleation. To understand these functions, we have tagged regulatory proteins with fluorescent proteins, and observed them in living cells of γ-tubulin mutant strains. We have uncovered a surprising role for γ-tubulin in regulating the inactivation of the anaphase promoting complex/cyclosome in the G1 phase of the cell cycle. Our genetic analyses indicate, moreover, that γ-tubulin has additional functions important for growth and reproduction.

To carry out this project in a timely fashion, we developed an extremely efficient gene targeting system for A. nidulans. This system was an important advance for the A. nidulans community and has had consequences well beyond this project. In my lab it has allowed us to carry out our second major project: to identify and characterize secondary metabolites from filamentous fungi, the genes involved in their biosynthesis, and the mechanisms by which their expression is regulated. Secondary metabolites are compounds that are not essential for viability, but they confer a selective advantage to the producing organism, often by inhibiting important biological activities in competing organisms in their ecosystem. The biological activities of fungal secondary metabolites are often medically useful, the classic example being the antibiotic penicillin, but there are many other examples including the statin family of cholesterol lowering agents.

The sequencing of the genomes of species of Aspergillus and other fungi revealed that they have the potential (based on the number of polyketide synthase and non-ribosomal peptide synthetase genes in the genome) to produce vastly more secondary metabolites than were known. In addition, the genes that encode the biosynthetic pathways for particular fungal secondary metabolites are usually clustered together in the genome, such that all of the genes involved in lovastatin biosynthesis, for example, are adjacent in the genome. The reason that the number of secondary metabolite gene biosynthetic clusters so greatly exceeds the number of known compounds is that most of them are not expressed under normal laboratory conditions. We have developed rapid gene targeting procedures for A. nidulans that allow us to delete genes or replace their promoters easily. This has allowed us to activate cryptic secondary metabolism pathways and, through deletion analysis, define the genes responsible for the synthesis of each secondary metabolite. We have also developed efficient procedures for expressing secondary metabolite gene clusters from other fungi in A. nidulans. Working with collaborators such as Clay Wang at the University of Southern California and Nancy Keller at the University of Wisconsin, we have discovered more than 100 new fungal secondary metabolites from A. nidulans and other species. Some of these have shown activities of potential value in treating cancer and tau-related neuropathies such as Alzheimer's disease.

Finally, our work on secondary metabolism and our gene targeting expertise has allowed us to create Aspergillus nidulans strains that produce useful compounds while growing on digestion products from waste plastics. Plastic pollution is a large and growing problem. Although some fungi can digest plastics, the process is currently too slow to have practical value. To overcome this problem, my lab in collaboration with the laboratories of Travis Williams and Clay Wang at USC, has developed a hybrid approach in which plastics are broken down to mono- and di-carboxylic acids by oxidative cleavage. We have engineered strains of A. nidulans that can use these acids as carbon sources and produce valuable compounds with remarkable efficiency.

Teaching

  • Cell biology
  • Genetics

Selected Publications

See all papers by Berl R Oakley on PubMed

 

  • Oakley, C. E., Barton, T. S. and Oakley, B. R. (2024) Identification of the chaA and fwA Spore Color Genes of Aspergillus nidulans. J Fungi 10, 104
  • Jenkinson, C. B., Podgorny, A. R., Zhong, C. and Oakley, B. R. (2023) Computer-aided, Resistance Gene-Guided Genome Mining for Proteasome and HMG-CoA Reductase Inhibitors. J Ind Microbiol Biotechnol 50, kuad045
  • Lin, S. Y. et al. (2023) A Heterologous Expression Platform in Aspergillus nidulans for the Elucidation of Cryptic Secondary Metabolism Biosynthetic Gene Clusters: Discovery of the Aspergillus fumigatus Sartorypyrone Biosynthetic Pathway. Chem Sci 14, 11022-11032
  • Rabot, C., Chen, Y., Lin, S. Y., Miller, B., Chiang, Y. M., Oakley, C. E., Oakley, B. R., Wang, C. C. C. and Williams, T. J. (2023) Polystyrene Upcycling into Fungal Natural Products and a Biocontrol Agent. J Am Chem Soc 145, 5222-5230
  • Zhang, J., Qiu, R., Bieger, B. D., Oakley, C. E., Oakley, B. R., Egan, M. J. and Xiang, X. (2023) Aspergillus SUMOylation Mutants Exhibit Chromosome-Segregation Defects Including Chromatin Bridges. Genetics 225, iyad169
  • Rabot, C., Chen, Y., Bijlani, S., Chiang, Y. M., Oakley, C. E., Oakley, B. R., Williams, T. J. and Wang, C. C. C. (2022) Conversion of Polyethylenes into Fungal Secondary Metabolites. Angew Chem Int Ed Engl e202214609
  • Yuan, B., Keller, N. P., Oakley, B. R., Stajich, J. E. and Wang, C. C. C. (2022) Manipulation of the Global Regulator mcrA Upregulates Secondary Metabolite Production in Aspergillus wentii Using CRISPR-Cas9 with In Vitro Assembled Ribonucleoproteins. ACS Chem Biol 17, 2828-2835
  • Ingham, D. J., Blankenfeld, B. R., Chacko, S., Perera, C., Oakley, B. R. and Gamblin, T. C. (2021) Fungally Derived Isoquinoline Demonstrates Inducer-Specific Tau Aggregation Inhibition. Biochemistry 60, 1658-1669
  • Lan, L., Liu, J., Xing, M., Smith, A. R., Wang, J., Wu, X., Appelman, C., Li, K., Roy, A., Gowthaman, R., Karanicolas, J., Somoza, A. D., Wang, C. C. C., Miao, Y., De Guzman, R., Oakley, B. R., Neufeld, K. L. and Xu, L. (2020) Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction. Cancers (Basel) 12, 2221
  • Grau, M. F., Entwistle, R., Oakley, C. E., Wang, C. C. C. and Oakley, B. R. (2019) Overexpression of an LaeA-like Methyltransferase Upregulates Secondary Metabolite Production in Aspergillus nidulans. ACS Chem Biol 14, 1643-1651
  • Dohn, J. W., Grubbs, A. W., Elizabeth Oakley, C. and Oakley, B. R. (2018) New Multi-Marker Strains and Complementing Genes for Aspergillus nidulans Molecular Biology. Fungal Genet Biol 111, 1-6
  • Grau, M. F., Entwistle, R., Chiang, Y. M., Ahuja, M., Oakley, C. E., Akashi, T., Wang, C. C. C., Todd, R. B. and Oakley, B. R. (2018) Hybrid Transcription Factor Engineering Activates the Silent Secondary Metabolite Gene Cluster for (+)-Asperlin in Aspergillus nidulans. ACS Chem Biol 13, 3193-3205
  • Paolillo, V., Jenkinson, C. B., Horio, T. and Oakley, B. R. (2018) Cyclins in aspergilli: Phylogenetic and functional analyses of group I cyclins. Stud Mycol 91, 1-22
  • Oakley, C. E., Ahuja, M., Sun, W. W., Entwistle, R., Akashi, T., Yaegashi, J., Guo, C. J., Cerqueira, G. C., Russo Wortman, J., Wang, C. C., Chiang, Y. M. and Oakley, B. R. (2017) Discovery of McrA, a master regulator of Aspergillus secondary metabolism. Mol Microbiol 103, 347-365
  • Kaur, K., Wu, X., Fields, J. K., Johnson, D. K., Lan, L., Pratt, M., Somoza, A. D., Wang, C. C. C., Karanicolas, J., Oakley, B. R., Xu, L. and De Guzman, R. N. (2017) The fungal natural product azaphilone-9 binds to HuR and inhibits HuR-RNA interaction in vitro. PLoS One 12, e0175471
  • Yeh, H. H., Ahuja, M., Chiang, Y. M., Oakley, C. E., Moore, S., Yoon, O., Hajovsky, H., Bok, J. W., Keller, N. P., Wang, C. C. and Oakley, B. R. (2016) Resistance Gene-Guided Genome Mining: Serial Promoter Exchanges in Aspergillus nidulans Reveal the Biosynthetic Pathway for Fellutamide B, a Proteasome Inhibitor. ACS Chem Biol 11, 2275-2284
  • Chiang, Y. M., Ahuja, M., Oakley, C. E., Entwistle, R., Asokan, A., Zutz, C., Wang, C. C. and Oakley, B. R. (2016) Development of Genetic Dereplication Strains in Aspergillus nidulans Results in the Discovery of Aspercryptin. Angew Chem Int Ed Engl 55, 1662-1665
  • Oakley, B. R., Paolillo, V. and Zheng, Y. (2015) γ-Tubulin complexes in microtubule nucleation and beyond. Mol Biol Cell 26, 2957-2962
  • Wang, B., Li, K., Jin, M., Qiu, R., Liu, B., Oakley, B. R. and Xiang, X. (2015) The Aspergillus nidulans bimC4 mutation provides an excellent tool for identification of kinesin-14 inhibitors. Fungal Genet Biol 82, 51-55
  • Paranjape, S. R., Riley, A. P., Somoza, A. D., Oakley, C. E., Wang, C. C., Prisinzano, T. E., Oakley, B. R. and Gamblin, T. C. (2015) Azaphilones inhibit tau aggregation and dissolve tau aggregates in vitro. ACS Chem Neurosci 6, 751-760
  • Edgerton, H., Paolillo, V. and Oakley, B. R. (2015) Spatial regulation of the spindle assembly checkpoint and anaphase-promoting complex in Aspergillus nidulans. Mol Microbiol 95, 442-457
  • Chiang, Y. M., Oakley, C. E., Ahuja, M., Entwistle, R., Schultz, A., Chang, S. L., Sung, C. T., Wang, C. C. C. and Oakley, B. R. (2013) An efficient system for heterologous expression of secondary metabolite genes in Aspergillus nidulans. J Am Chem Soc 135, 7720-7731
  • Edgerton-Morgan, H. and Oakley, B. R. (2012) γ-Tubulin plays a key role in inactivating APC/CCdh1 at the G1-S boundary. J Cell Biol 198, 785-791
  • Taheri-Talesh, N., Xiong, Y. and Oakley, B. R. (2012) The Functions of Myosin II and Myosin V Homologs in Tip Growth and Septation in Aspergillus nidulans. PLoS One 7, e31218
  • Somoza, A. D., Lee, K. H., Chiang, Y. M., Oakley, B. R. and Wang, C. C. C. (2012) Reengineering an azaphilone biosynthesis pathway in Aspergillus nidulans to create lipoxygenase inhibitors. Org Lett 14, 972-975
  • Ahuja, M., Chiang, Y. M., Chang, S. L., Praseuth, M. B., Entwistle, R., Sanchez, J. F., Lo, H. C., Yeh, H. H., Oakley, B. R. and Wang, C. C. C. (2012) Illuminating the diversity of aromatic polyketide synthases in Aspergillus nidulans. J Am Chem Soc 134, 8212-8221
  • Nayak, T., Edgerton-Morgan, H., Horio, T., Xiong, Y., De Souza, C. P., Osmani, S. A. and Oakley, B. R. (2010) γ-Tubulin regulates the anaphase-promoting complex/cyclosome during interphase. J. Cell Biol. 190, 317-330
  • Xiong, Y. and Oakley, B. R. (2009) In vivo analysis of the functions of γ-tubulin-complex proteins. J. Cell Sci. 122, 4218-4227
  • Taheri-Talesh, N., Horio, T., Araujo-Bazan, L., Dou, X., Espeso, E. A., Penalva, M. A., Osmani, S. A. and Oakley, B. R. (2008) The tip growth apparatus of Aspergillus nidulans. Mol Biol Cell 19, 1439-1449
  • Nayak, T., Szewczyk, E., Oakley, C. E., Osmani, A., Ukil, L., Murray, S. L., Hynes, M. J., Osmani, S. A. and Oakley, B. R. (2006) A versatile and efficient gene-targeting system for Aspergillus nidulans. Genetics 172, 1557-1566
  • Prigozhina, N. L., Oakley, C. E., Lewis, A., Nayak, T., Osmani, S. A. and Oakley, B. R. (2004) γ-Tubulin plays an essential role in the coordination of mitotic events. Mol Biol Cell 15, 1374-1386
  • Ovechkina, Y., Maddox, P., Oakley, C. E., Xiang, X., Osmani, S. A., Salmon, E. D. and Oakley, B. R. (2003) Spindle formation in Aspergillus is coupled to tubulin movement into the nucleus. Mol Biol Cell 14, 2192-2200
  • Jung, M. K., Prigozhina, N., Oakley, C. E., Nogales, E. and Oakley, B. R. (2001) Alanine-scanning mutagenesis of Aspergillus γ-tubulin yields diverse and novel phenotypes. Mol Biol Cell 12, 2119-2136
  • Wise, D. O., Krahe, R. and Oakley, B. R. (2000) The γ-tubulin gene family in humans. Genomics 67, 164-170
  • Khodjakov, A., Cole, R. W., Oakley, B. R. and Rieder, C. L. (2000) Centrosome-independent mitotic spindle formation in vertebrates. Curr Biol 10, 59-67
  • Wilson, P. G., Zheng, Y., Oakley, C. E., Oakley, B. R., Borisy, G. G. and Fuller, M. T. (1997) Differential expression of two γ-tubulin isoforms during gametogenesis and development in Drosophila. Develop Bio 184, 207-221
  • Horio, T. and Oakley, B. R. (1994) Human γ-tubulin functions in fission yeast. J Cell Biol 126, 1465-1473
  • Zheng, Y., Jung, M. K. and Oakley, B. R. (1991) γ-tubulin is present in Drosophila melanogaster and Homo sapiens and is associated with the centrosome. Cell 65, 817-823
  • Oakley, B. R., Oakley, C. E., Yoon, Y. and Jung, M. K. (1990) γ-Tubulin is a component of the spindle pole body that is essential for microtubule function in Aspergillus nidulans. Cell 61, 1289-1301
  • Oakley, C. E. and Oakley, B. R. (1989) Identification of γ-tubulin, a new member of the tubulin superfamily encoded by mipA gene of Aspergillus nidulans. Nature 338, 662-664
  • Oakley, B. R. and Morris, N. R. (1983) A mutation in Aspergillus nidulans that blocks the transition from interphase to prophase. J Cell Biol 96, 1155-1158
  • Oakley, B. R. and Morris, N. R. (1981) A β-tubulin mutation in Aspergillus nidulans that blocks microtubule function without blocking assembly. Cell 24, 837-845
  • Oakley, Berl R. and Morris, N. R. (1980) Nuclear movement is β-tubulin-dependent in Aspergillus nidulans. Cell 19, 255-262
  • Oakley, B. R., Kirsch, D. R. and Morris, N. R. (1980) A simplified ultrasensitive silver stain for detecting proteins in polyacrylamide gels. Anal Biochem 105, 361-363
  • Oakley, B. R. and Dodge, J. D. (1974) Kinetochores associated with the nuclear envelope in the mitosis of a dinoflagellate. J Cell Biol 63, 322-325
  • Oakley, B. R. and Dodge, J. D. (1973) Mitosis in the Cryptophyceae. Nature 244, 521-522