Department of Molecular Genetics

The Department of Molecular Genetics, which includes the Section of Virology, was established in 1987 with the mission to build the programmatic and methodological infrastructure of molecular biology within the Research Institute and to stimulate research on the structure, regulation and mechanisms of activity of viral and cellular genes. Since then, the Department has developed into a strong academic union of nationally recognized experts representing a broad spectrum of disciplines. It maintains the spirit of collegiality and mutual support, has a solid technical infrastructure and is efficiently run by an experienced administrative team. Ongoing research programs cover the following areas.

Understanding the molecular mechanisms of stress-, cytokine-, and oncogene-mediated signal transduction remains a major area of research within the Department. George R. Stark's and Ganes C. Sen's laboratories have a long-standing interest in deciphering mechanisms by which interferon (IFN)-mediated signaling occur in mammalian cells via activation of various signal transducers, resulting in changes in gene expression. Stark's team, in addition, is working on understanding the mechanisms of activation of NFkB by various stresses and its effects on cellular growth regulation. Sen's laboratory is involved in determining functional characteristics of several IFN-induced proteins as well as signaling initiated by double-stranded RNA. In addition, pathways involved in viral apoptosis are being delineated. Another area of interest is the analysis of specific physiological roles of different isoforms of angiotensin -converting enzymes using engineered mouse strains that express the protein in tissue specific fashions. Dennis W. Stacey's laboratory is focused on the role of oncogene ras-mediated signaling and topoisomerase II expression in control of cell cycle and cell response to chemotherapeutic drugs. The group develops and applies unique experimental approaches to the analysis of the cell cycle allowing revision of established dogmas in this highly competitive field.

The laboratories of two staff members are involved in understanding most basic mechanisms of cellular RNA synthesis and processing. Donal S. Luse leads a team that studies transcription by RNA polymerase II with specific focus on promoter clearance and regulation of initial steps of transcript elongation. Richard A. Padgett primarily focuses his studies on the molecular mechanisms of RNA splicing, including the chemistry of this process, identification of cellular factors involved in control of RNA splicing and evolution of splicing machinery.

Kurt W. Runge continues work on the replication and maintenance of telomeres, the physical ends of eukaryotic chromosomes, using budding yeast as a model organism. Besides understanding telomere structure and function, his work provides insights into the mechanisms of cellular aging, and the control of malignant transformation and is evolving towards development of new cancer treatment approaches.

Jocelyn A. McDonald uses a combination of modern genetics and molecular, developmental and cell biology to identify genes that regulate cell migration during development, in the model organism, Drosophila melanogaster. Michelle S. Longworth’s laboratory utilizes the model organism, Drosophila, and human tissue culture cells to study the regulation of global chromatin structure by the Condensin II complex. The lab also uses techniques in genetics, biochemistry and molecular biology to identify novel Condensin II interactions and characterize how the complex regulates transcription.

The major advance for the past decade in science is that human genome sequence become available to the public. Constant risk from inside, such as reactive oxygen species or outside, such as ultraviolet light, endangers the integrity of our genome. One very dangerous form of damage is breakage of the genome sequence (DNA double strand break). Hisashi Tanaka's research goal is to determine how cellular mechanism protects our genome from DNA double strand break and how failure of maintaining integrity of the genome leads to cancer using our very unique genome-wide approach.

Eain A. Murphy studies the roles of viral and host microRNAs in human cytomegalovirus virus pathogenesis, which is a major problem in organ transplantation. The recent discovery of microRNAs has revolutionized our understanding of the mechanisms of regulation of cellular and viral gene expression. These highly abundant small RNAs bind to specific mRNAs and block their translation to proteins. Enhancement of this natural regulatory system has the potential to be therapeutically valuable.

Brian Rubin is interested in cancer biology with an emphasis on the study of sarcomas. His lab uses a variety of approaches to identify cancer causing oncogenes, study their functions, and eventually identify therapies that target them.

In summary, the Department of Molecular Genetics combines basic and translational research covering a whole range of problems, from understanding the basics of cell regulation to development of clinically useful pharmaceuticals. Our productive laboratories, led by nationally recognized principal investigators, are taking a well-defined course towards strengthening disease-oriented translational research programs in collaboration with other divisions of the Cleveland Clinic.

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