Ron Conaway Lab

Ron Conaway, Ph.D.

Investigator

Professor, Department of Biochemistry & Molecular Biology
  The University of Kansas School of Medicine

 

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Ron Conaway, Ph.D., and Joan Conaway, Ph.D, know how to do science the old-fashioned way. Almost three decades ago they teamed up to carry out the kind of column-packing, rotor-toting, get-dirty biochemistry that finds you in the lab at 2 in the morning. Their reward was no less than a body of work defining how the enzyme RNA polymerase II (pol II) catalyzes transcription of mRNA, the fundamental requirement for gene expression.  

The two married while graduate students and started working together when Ron, having earned a Ph.D. in the early 80’s in the lab of I. Robert Lehman at Stanford,was postdoc’ing at the DNAX Research Institute in Palo Alto, and Joan was a graduate student in Roger Kornberg’s lab at Stanford. Although the pol II enzyme had been purified, by itself it was not sufficient to drive mRNA synthesis in a test tube, suggesting it lacked “initiating” factors. “Roger said ‘Why don’t you two work together to see if you can isolate those factors,’” remembers Ron.

The start of their collaboration officially launched the “The Conaways” as a transcriptional force. Four years and one disaster later (a very hard-earned prep of TFIIB peptide “disappeared” on a chromatography column, never to be seen again), the pair reported in a 1987 JBC paper the first biochemical purification of a mammalian initiation factor—TFIIB—isolated from rat liver.

By 1991, the team had purified three more factors, including TFIIF, E, and H, which when combined with TFIIB, pol II, and one more factor, TBP, accomplished a first: the creation of a system capable of initiating transcription in vitro with pure proteins. That feat was published in 1991 as a set of three JBC papers.Those efforts—along with parallel efforts by groups working in yeast, flies and cultured cells—constitute what a 2005 issue of Nature called a “milestone of gene expression.”

In 1989 the Conaways took faculty positions at the Oklahoma Medical Research Foundation, where they began to focus on proteins that increase the rate at which mRNA strands elongate. Among them were Elongin, reported in a 1995 Science paper, and the protein ELL, reported in Science in 1996 and purified by their postdoc Ali Shilatifard, now a Stowers investigator himself.

Several of the genes encoding for elongation factors were known to undergo chromosomal translocations fusing them to a gene called MLL creating potent leukemia-causing hybrid genes. “The ELL story was one of those wonderful circumstances in which people who study cancer come from one direction and intersect with basic researchers like us coming from another,” says Joan. “What it suggested was that dysregulated transcriptional elongation can contribute to cancer.”

During that period they also began working on another intriguing link to cancer when they reported in a 1995 Science paper that a tumor suppressor known as the von Hippel-Lindau (VHL) protein forms a complex with two subunits of Elongin, called Elongin B and Elongin C. Since then, the VHL complex has been shown to be involved in the so-called ubiquitin-proteasome degradation pathway and thereby to control levels of a transcription factor that plays a key role in oncogenesis.

The Conaways have continued their studies of VHL and elongation factors at Stowers, where they were recruited as investigators in 2001, and have also turned their attention to another multi-protein complex that co-regulates pol II, known in yeast as the Mediator. Often collaborating with Michael Washburn and Laurence Florens in the Proteomics Center at the Stowers Institute, they have used an approach called MudPIT to define the full complement of roughly 30 mammalian Mediator subunits, published in 2005 in Molecular Cell.
Those studies led to the recent discovery that one of the Mediator subunits, Med26, controls expression of a collection of genes by recruiting a so-called “super elongator” complex. These studies, published in 2011 in Cell, show that MED26 acts as a molecular switch linking factors of the Pol II complex to separate proteins that carry out mRNA elongation.

In recognition of their achievements Joan was named Associate Investigator of the Howard Hughes Medical Institute between 1997 and 2001. Both Ron and Joan received the American Society for Biochemistry and Molecular Biology/Amgen Award in 1997 and were elected in 2002 to the American Academy of Arts and Sciences.

Raised in Montana, Ron earned an AB degree in physics and chemistry from Indiana University and fell only one course short of adding a degree in philosophy as well. Joan, whose parents were biochemists, grew up in New York and received her AB in chemistry and biology from Bryn Mawr College. She confesses to not being particularly “introspective” about where their motivation comes from, saying simply, “We just really enjoy tearing into biochemical questions!”

“We” is the operative pronoun. Although they can probably name every Mediator subunit, the Conaways are at a loss when asked to name different strengths they bring to running a lab. “We go to meetings together but Joan does all the talking,” says Ron, when forced to come up with something. And Joan adds, "But Ron writes the first draft of grants and most of the papers, so I get off easy!"

Neither works much at the bench now, but Ron especially seems nostalgic for the “heyday of recombinant DNA technology at Stanford, when we made our own restriction enzymes in the lab.”  So both he and Joan lend a hand in the purification process when the lab needs to restock its pol II protein supply. “The yields just seem better if we do it,” says Ron.