Heads of Laboratories
The first step in the synthesis of proteins is transcription of RNA. But in all eukaryotes, between the time when RNA is made and when it is translated into proteins, it often undergoes a process called splicing, when certain parts of the RNA (called introns) are cut out and the remaining sequences (called exons) are joined back together. How RNA splicing occurs, and the interplay between splicing and transcription, is the subject of Dr. Konarska’s research.
Using a combination of yeast genetics and biochemistry, Dr. Konarska is interested in what happens to messenger RNA before and as it is spliced. More specifically, her laboratory is interested in how the spliceosome (the large complex responsible for splicing catalysis, composed of hundreds of proteins and five small RNA molecules) is formed and how it functions, i.e., what happens at the catalytic center of the spliceosome during the removal of introns. Dr. Konarska also examines the connection between RNA transcription and splicing.
Multiple interactions between the different proteins and RNAs of the spliceosome are important for creating an active catalytic site for splicing. The splicing process requires a series of conformational rearrangements of the spliceosome that affect its assembly, catalysis and disassembly. In collaboration with Charles Query at the Albert Einstein College of Medicine, Dr. Konarska has recently formulated a two-state model of spliceosome function, according to which structural conformations that define the two catalytic steps exist in competition with one another. This model suggests remarkable similarities between the mechanism of function of the ribosome (another large ribonucleoprotein complex, which catalyzes protein synthesis) and the spliceosome. In both cases, equilibrium between conformational states can be modulated by many factors, including, but not limited to, specific contacts between the RNA substrate and the enzyme.
The spliceosome is able to act on suboptimal splice sites, especially in higher eukaryotes, but to an extent also in yeast. According to the two-state model of spliceosome function, selection of suboptimal sites may be improved by many factors that modulate the relative stabilities of conformational states of the spliceosome. Many mutated forms of various spliceosomal proteins affect splicing in this way, as may alternative splicing factors that improve splicing of certain entire classes of introns. A separate project in the lab looks at other molecules (RNA or small chemical molecules) that stabilize specific conformations of the spliceosome. These molecules would functionally resemble ribosomal antibiotics that inhibit translation by binding to the ribosome and stabilizing one of the two alternative conformations. Once identified, such “splicing antibiotics” would provide tools for biochemical and structural studies of the spliceosome and may have therapeutic applications.
Although Dr. Konarska’s research addresses the basic function of the spliceosome and the mechanism of splicing catalysis in yeast, these findings elucidate general properties of splicing in all eukaryotes, including humans. Therefore, these results help scientists understand not only the splicing of canonical introns, but also of those that undergo the alternative splicing typical of mammalian cells. In this way, Dr. Konarska’s research may help uncover the etiology of multiple genetic disorders resulting from changes in alternative splicing patterns of specific gene transcripts. In addition, a better understanding of RNA splicing may shed light on the origins of life, as some models propose that the earliest organisms used RNA or an RNA-like molecule rather than DNA as their genetic material.
Dr. Konarska was born in Poland and received her M.Sc. in genetics from the University of Warsaw in 1979. In 1983, she received her Ph.D. in biochemistry from the Institute of Biochemistry and Biophysics at the Polish Academy of Sciences in Warsaw. She joined the Center for Cancer Research at the Massachusetts Institute of Technology (MIT) as a postdoc in 1984 and became a research associate at MIT in 1987. Dr. Konarska came to The Rockefeller University as assistant professor in 1989 and became associate professor in 1994 and professor in 2000.
In 1992, Dr. Konarska received the Monique Weill-Caulier Career Scientist Award. She received the Lucille P. Markey Scholar Award in 1987 and the Jakub Karol Parnas Award of the Polish Biochemical Society in 1985.
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