The Luse Lab focuses on critical molecular mechanisms involved in RNA synthesis by RNA polymerase II (Pol II). These include assembly of the transcription complex at promoters, transcript initiation and promoter clearance, efficient elongation of nascent RNA chains and the interaction of the transcriptional machinery with nucleosomes, both at the level of preinitiation complex assembly and downstream during transcript elongation.
Our laboratory has made major contributions in all these areas. We have a long-standing and productive collaboration with David Price’s laboratory (University of Iowa) on investigations into the early stages of transcription. As an example, this effort led to the first unified description of the Pol II promoter at the sequence level, its connection to downstream pausing and its relationship to the local chromatin structure.
Most recently, our group has shown using in vitro methods that the general transcription factor TFIID has an unexpectedly significant role in the ability of promoter-proximal nucleosomes to inhibit transcription complex assembly, an effect which depends on the sequence of the Pol II promoter itself and on histone modifications in the promoter-proximal nucleosomes. I hope to build on my existing expertise to further understand the role of the chromatin architecture of Pol II promoters in controlling transcription complex assembly and the advance of the RNA polymerase into the fully elongation-competent form.
Donal Luse, PhD, is an expert in RNA synthesis and the relationship of chromosome structure and gene regulation. Dr. Luse serves as an adjunct professor of biochemistry and professor of molecular medicine at the Cleveland Clinic Lerner College of Medicine. He has sat on the editorial board for the Journal of Biological Chemistry several times since 1993 (1993-1998; 1999-2004; 2013-2022). Dr. Luse earned his BA and PhD in biophysics from Johns Hopkins University. He then went on to Washington University in St. Louis where he was a postdoctoral fellow in the department of biological chemistry. Dr. Luse was a professor at University of Cincinnati College of Medicine for 13 years before joining the Lerner Research Institute in 1994.
1994- present Cleveland Clinic, Lerner Research Institute
Staff Member, 1994-2015, Dept. of Molecular Genetics
2015-2018, Dept. of Cellular and Molecular Medicine
2018-present, Dept. of Cardiovascular and Metabolic Sciences
1994- present Case Western Reserve University School of Medicine
Adjunct Professor of Biochemistry
Since 2005, Professor of Molecular Medicine in the Cleveland Clinic Lerner College of Medicine
1981-1994 University of Cincinnati College of Medicine
Assistant Professor (Biological Chemistry), 1981-1986
Associate Professor (Biochemistry and Molecular Biology), 1986-1993
Professor (Molecular Genetics, Biochemistry and Microbiology), 1993-1994
1978-1981 Postdoctoral Fellow, Dept. of Biological Chemistry, Washington Univ., St. Louis
1978 PhD, Biophysics, Johns Hopkins University
1973 B.A., Biophysics, Johns Hopkins University
With very few exceptions, all cells in our bodies contain the same genetic information within their DNA. However, each cell utilizes only a very specific subset of the roughly 20,000 human genes. The mechanisms which select the cohort of genes to be read and determine their relative expression remain poorly understood, despite the critical importance of those decisions for human health.
Gene expression begins with copying of the DNA information into an RNA messenger intermediate. The RNA synthesis machinery, which consists of RNA polymerase II (Pol II) and a complex array of accessory factors, must first find the correct starting point (the promoter) for each gene. Promoter recognition and subsequent transcription takes place despite generally tight DNA packaging by the chromosomal proteins.
Our laboratory uses test tube systems to study the molecular events that drive promoter recognition and transcription of genes within the context of chromosomes. Our overall aim is to biochemically dissect the early stages of transcription to understand the mechanistic basis for distinct outcomes for Pol II complexes within the local chromatin context.
The primary questions our lab is trying to answer through our research are:
How does local chromosome structure control the assembly of Pol II at promoters?
Chromosome structure is composed of extended arrays of protein-DNA complexes called nucleosomes, each occupying about 150 base pairs along the DNA. It is not fully understood how nucleosome locations proximal to promoters affect the ability of the transcription complex to access critical sequences. The histone proteins which fold DNA into nucleosomes are chemically modified in patterns which correlate with gene activity, but the functions of these modifications are largely unknown. Our recent results have provided unanticipated insight into these questions. A major focus of our upcoming research will be to expand on those findings to determine how the local chromosome structure at promoters determines the effectiveness of transcription complex assembly.
How is the fate of early elongation complexes determined?
It is well established that once RNA synthesis is underway, most transcription complexes turn over within about the first 50 base pairs downstream of the start of transcription; only a minority of the RNA polymerases advance to generate the RNA message. This represents a major control point for gene expression. The decision to either terminate or advance into productive elongation typically occurs near the point at which Pol II must begin to traverse DNA wrapped on the initial downstream nucleosome, suggesting that this encounter influences the terminate/advance process. Many protein factors have also been described which can stimulate or repress the advance of Pol II into the gene. It is not understood how the interplay of these factors and the local chromosome structure determines the extent to which newly initiated Pol II can enter productive elongation. Through in vitro experiments, we recently developed novel methods to study the terminate/advance reactions in a chromosomal context. Using these approaches should allow us to significantly extend our understanding of the mechanisms that competitively determine the fate of Pol II complexes immediately following the initiation of transcription.
Fisher, M.J. and Luse, D.S. (2024) Defining a chromatin architecture that supports transcription at RNA polymerase II promoters. J. Biol. Chem. 300 (8), 107515
Santana, J.F., Spector, B.M., Suarez, G.A., Luse, D.S. and Price, D.H. (2024) NELF Focuses Sites of Initiation and Maintains Promoter Architecture, Nucleic Acids Research 52, https://doi.org/10.1093/nar/gkad1253 PMID: 38197272
Fisher, M.J. and Luse, D.S. (2023) Promoter proximal nucleosomes attenuate RNA polymerase II transcription through TFIID, J. Biol. Chem. 299, 104928 PMID: 37330174 PMCID: PMCID: PMC10404688
Santana, J.F., Collins, G., Parida, M., Luse, D.S. and Price, D.H. (2022) Differential dependencies of human RNA polymerase II promoters on TBP, TAF1, TFIIB, and XPB. Nucleic Acids Research 50, 9127–9148 PMID: 35947745, PMCID: PMC9458433
Spector, B.M., Parida, M., Li, M., Ball, C.B., Meier, J.L., Luse, D.S. and Price, D.H. (2022) Differences in RNA Polymerase II Complexes and Surrounding Chromatin on Host and Cytomegalovirus Genomes are Revealed by DFF-Chip. Nature Communications 13, 2006 PMID: 35422111 PMCID: PMC9010409
Luse, D.S., Parida, M., Spector, B.M., Nilson, K.A., and Price, D. H. (2020) A Unified View of the Sequence and Functional Organization of the Human RNA Polymerase II Promoter, Nucleic Acids Research 48, 7767-7785. PMID: 32597978, PMCID: PMC7641323
Li, M., Ball, C.B., Collins, G., Hu, Q., Luse, D.S., Price, D.H. and Meier, J.L. (2020) Human cytomegalovirus IE2 drives transcription initiation from a unique class of viral late promoters, PLOS Pathogens 16 (4): e1008402. PMID: 32251483, PMCID: 7162547
Luse, D.S. (2019) How does RNA polymerase II escape the promoter? Proc. Nat. Acad. Sci. USA 117, 22426-22428. PMID: 31628251, PMCID: 6842580
Parida, M, Nilson, K.A., Li, Ming, Ball, C.B., Fuchs, H.A., Lawson, C.K., Luse, D.S., Meier, J.L. and Price, D.H. (2019) Nucleotide-resolution comparison of transcription of human cytomegalovirus and host genomes reveals universal use of RNA polymerase II elongation control driven by dissimilar core promoter elements. mBio 10, DOI: 10.1128/mBio.02047-18. PMID: 30755505 PMCID: 6372792
DeLaney, E. and Luse, D.S. (2016) Gdown1 Associates Efficiently with RNA Polymerase II after Promoter Clearance and Displaces TFIIF During Transcript Elongation. PLoS ONE, 11(10): e0163649. PMID: 27716820 PMCID: PMC5055313
Nilson, K.A., Guo, J., Turek, M.E., Brogie, J.E., DeLaney, E., Luse, D.S and Price, D.H. (2015) THZ1 reveals roles for Cdk7 in co-transcriptional capping and pausing. Molecular Cell 59, 576-587 PMID: 26257281 PMCID: PMC4546572
Davis, M.A.M., Guo,J., Price, D.H. and Luse, D.S. (2014) Functional interactions of the RNA polymerase II-interacting proteins Gdown1 and TFIIF, J. Biol. Chem. 289, 11143-11152. PMID: 24596085 PMCID: PMC4036253
Luse, D.S. (2013) The RNA polymerase II preinitiation complex: through what pathway is the complex assembled? Transcription 5 (1):e27050. doi: 10.4161/trns.27050. PMID: 24406342 PMCID: PMC4214227
Luse, D.S. (2013) Promoter clearance by RNA polymerase II. BBA Gene Regulatory Mechanisms 1829, 63-68. PMID: 22982364 PMCID: PMC3529798
Luse, D.S. (2012) Rethinking the role of TFIIF in transcript initiation by RNA polymerase II. Transcription 3, 156-159. PMID: 22771986 PMCID: PMC3654762
Čabart, P. and Luse, D.S. (2012) Inactivated RNA polymerase II open complexes can be reactivated with TFIIE. J. Biol. Chem. 287, 961-967. PMID: 22119917 PMCID: PMC3256861
Čabart, P., Újvári, A., Pal, M. and Luse, D.S. (2011) Transcription factor TFIIF is not required for initiation by RNA polymerase II but it is essential to stabilize transcription factor TFIIB in early elongation complexes. Proc. Nat. Acad. Sci. USA 108, 15786-15791. PMID:21896726 PMCID: PMC3179120
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