Steven Hanes, PhD
RESEARCH PROGRAMS AND AFFILIATIONS
Model Genes in Model Organisms
Gene Regulation in Development and Disease: My laboratory is interested in how cells control the activity of genes during early development of the embryo and during the cell cycle. One key point of regulation is the synthesis of an RNA copy of individual genes. This process is carried out by RNA polymerase II (RNA pol II). We study RNA pol II in two distinct contexts (see below). Each project uses a different model organism to its best advantage, where we can apply sophisticated genetic, molecular, and biochemical tools to discover important mechanisms of gene regulation. Our findings are relevant to understanding similar mechanisms that occur in human cells, and whose disruption is often associated with disease.
Homeobox genes: In the first project we study homeobox transcription regulators in Drosophila melanogaster (fruit fly). For example, we study a homeobox gene called bicoid, which encodes a protein (Bicoid) that directs development of the head and thorax in early embryos. Bicoid works by recruiting RNA pol II to selected target genes, and how exactly it does this is the subject of our work. Our results have been important for understanding how homeobox genes function in normal cells and how their disruption causes certain human cancers (e.g. childhood leukemias). We also discovered proteins that interact with Bicoid (Sap18 and Bin3). These proteins have human counterparts and we are trying to understand how they function.
Prolyl isomerases: In a second project, we study a gene called ESS1 in Saccharomyces cerevisiae (yeast), which encodes an enzyme known as a prolyl-isomerase. ESS1 is essential for growth in yeast and cells that lack ESS1 arrest in mitosis. A counterpart of ESS1 is found in humans and is called PIN1. We are learning how yeast ESS1 and human PIN1 control cell growth. We discovered that Ess1 works by controlling the conformation of RNA pol II. This understanding might lead to the development of antifungal drugs (or anticancer drugs for PIN1). Toward this goal, we isolated ESS1 homologs from Candida albicans and Cryptococcus neoformans, the two major human fungal pathogens. Ess1 in these organisms is important for virulence, so we are working toward an eventual goal of targeting Ess1 for inhibition as a potential antifungal treatment.
Palumbo, R. J., McKean, N., Leatherman, E., Namitz, K. E. W, Connell, L., Wolfe, A., Moody, K., Gostinčar, C., Gunde-Cimerman, N., Bah, A., and Hanes, S. D. (2022). Co-evolution of the Ess1-CTD axis in polar fungi suggests a role for phase separation in cold tolerance. Sci Advances Vol 8, Issue 36, eabq3235, 7 Sept, DOI: 10.1126/sciadv.abq3235
Namitz, K. E. W. , Zheng, T., Canning, A. J., Alicea-Velazquez, N. L., Castañeda, C. A. and Cosgrove, M. C., and Hanes, S. D. (2021) Structure analysis suggests Ess1 isomerizes the carboxy-terminal domain of RNA polymerase II via a bivalent anchoring mechanism. Nat. Comms Biol. 4:398 https://doi.org/10.1038/s42003-021-01906-8
- Hanes, S. D. (2015). Prolyl isomerases in gene transcription. (Review) BBA General Subjects (Open Access, published online Oct. 31, 2014).
- Allepuz-Fuster, P., Martinez-Fernandez, V. Garrido-Godino, A.I, Alonso-Aquado, S. Hanes, S.D., Navarro, F. and Calvo, O. (2014). Rpb4/7 facilitates RNA polymerase II CTD dephosphorylation. Nuc. Acids Res. 42: 13674-88.
- Hanes, S. D. (2014). The Ess1 prolyl isomerase: Traffic cop of the RNA polymerase II transcription cycle. (Review) BBA Gene Regulatory Mechanisms 1839: 316-333.
- Atencio, D., Barnes, C., Duncan, T. M., Willis, I. M, and Hanes S. D. (2014). The yeast Ess1 prolyl isomerase controls Swi6 and Whi5 nuclear localization. Genes, Genomes, Genetics 4: 523-537.
- Samaranayake, D., Atencio, D., Morse, R., Wade, J.T., Chaturvedi, V., and Hanes, S.D. (2013). Role of Ess1 in growth, morphogenetic switching, and RNA polymerase II transcription in Candida albicans. PLoS ONE, March 14, 8(3):e59094.
- Ma, Z., Atencio D., Barnes, C., DeFiglio, H., and Hanes, S. D. (2012) Multiple Roles for the Ess1 Prolyl Isomerase in the RNA Polymerase II Transcription Cycle. Mol. Cell. Biol. 32: 3594-3607.
- Cosgrove, M., Ding, Y., Rennie, W. A., Lane, M. J., and Hanes, S. D. (2012). The Bin3 RNA methyltransferase (MePCE) targets 7SK RNA to control transcription and translation. WIRES-RNA (Review) (Wiley) July 12, PMID:22740346
- Battaile, A. R., Jeronimo, C., Jacques P-E., Laramee, L., Fortin, M-E., Forest, A., Bergeron, M., Hanes, S. D., and Robert, F. (2012). A universal RNA polymerase II CTD cycle is orchestrated by complex interplays between kinase, phosphatase, and isomerase enzymes along genes. Mol. Cell 45: 158-170.
- Samaranayake, D. P., and Hanes, S. D. (2011). Milestones in Candida albicans gene manipulation. (Review) Fungal Genet & Biol. 48: 858-865.
- Singh, N., Morlock, H. and Hanes, S. D. (2011). The Bin3 RNA methyltransferase is required for caudal repression in the Drosophila embryo. Devel. Biol. 352: 104-115.
- McNaughton, L., Li, Z., Van Roey, P., Hanes, S.D., and LeMaster, D. (2010). Restricted domain mobility in the Candida albicans Ess1 prolyl isomerase. Biochim. Biophys. Acta 1804: 1537-1541.
- Singh, N., Ma, Z., Gemmill, T., Wu, X., Rossettini, A., Rabeler, C., Beane, O., DeFiglio, H., Palumbo, M., Morse, R. and Hanes, S.D. (2009). The Ess1 prolyl isomerase is required for transcription termination of small non-coding regulatory RNAs via the Nrd1 pathway. Mol. Cell, 36: 255-266.
- Li, Z., Li, H-M., Devasahayam, G., Gemmill, T., Chaturvedi, V., Hanes, S. D., and Van Roey, P. (2005). Structure of the Candida albicans Ess1 prolyl isomerase reveals a well-ordered linker region that restricts domain mobility. Biochemistry 44: 6180-6189.
- Singh, N., Zhu, W. and Hanes, S. D. (2005). Sap18 is required for the maternal gene bicoid to direct anterior patterning in Drosophila melanogaster. Devel. Biol. 278; 242-254.
- Lebrecht, D., Foehr, M., Smith, E., Lopes, F. J. P., Vanario-Alonso C. E., Reinitz, J., Burz, D. S., and Hanes, S. D. (2005). Bicoid cooperative DNA binding is critical for embryonic patterning in Drosophila. Proc. Natl. Acad. Sci. USA 102: 13176-13181.
- Wu, X., Rossettini, A. and Hanes, S. D. (2003). The ESS1 prolyl isomerase and its suppressor BYE1 interact with RNA pol II to inhibit transcription elongation in Saccharomyces cerevisiae. Genetics 165: 1687-1702.
- Devasahayam, G., Chaturvedi, V. and Hanes, S. D., (2002). The Ess1 prolyl-isomerase is required for growth and morphogenetic switching in Candida albicans. Genetics 160: 37-48.
- Zhu, W., Foehr, M., Jaynes, J. B., and Hanes, S. D. (2001). Drosophila SAP18, a member of the Sin3/Rpd3 histone deacetylase complex interacts with Bicoid and inhibits its activity. Dev. Genes Evol. 211: 109 – 117.
- Burz, D. S. and Hanes, S. D. (2001). Isolation of mutations that disrupt cooperative DNA binding by the Drosophila Bicoid protein. J. Mol. Biol. 305: 219-230.
- Wu, X., Wilcox, C. B., Devasahayam, G., Hackett, R.L., Arevalo-Rodriguez, M., Cardenas, M., Heitman, J., and Hanes, S. D. (2000). The Ess1 prolyl-isomerase is linked to chromatin remodeling complexes and the general transcription machinery. EMBO J. 19: 3727-3738. (selected for "Editor's Choice" section, Science, 289:833)
- Burz, D.S., Rivera-Pomar, R., Jackle, H., and Hanes, S.D. (1998). Cooperative DNA binding by Bicoid provides a mechanism for threshold-dependent activation in the Drosophila embryo. EMBO J. 17: 5998-6009.
- Lu, K. P., Hanes, S. D., and Hunter, T. (1996). A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380: 544-547.