Genetics, Vol. 169, 506-507, February 2005, Copyright © 2005

The 2005 Genetics Society of America Medal

James E. Haber

THE 2005 GSA Medal is awarded to Steven J. Elledge for his seminal contributions to the study of the regulation of the cell cycle, especially in cellular responses to DNA damage. One of the most impressive aspects of Elledge's work has been the facility with which he and his colleagues have carried out studies both with a model organism, budding yeast Saccharomyces cerevisiae, and with mammalian cells. In both cases he has combined powerful genetic screens with innovative molecular biology and biochemistry to characterize the way cell cycle progression is coordinated and regulated. In addition to the many genes and regulatory pathways his lab has identified and characterized, Steve Elledge has enriched his colleagues by his passion for the development of many genetic tools and reagents.

Elledge's interest in the way cells cope with DNA damage began with his graduate work with Graham Walker at MIT, where he identified the UmuC bypass DNA polymerase. During this time Elledge also developed phasmids, the first of several novel recombinant DNA-cloning systems he has devised. Steve's interest in biotechnology drew him to the lab of Ron Davis, at Stanford, in 1984. There, he devised several new genetic tools, including both shuttle vectors allowing easier cloning and transfer of genes from yeast to Escherichia coli and an inducible gene library that made possible the study of dominant mutations. But his future direction was launched by a fortuitous result: While trying to clone the yeast homolog of the bacterial recombinase Rec A, Elledge instead identified a subunit of ribonucleotide reductase. With his finding that the RNR genes were both cell cycle regulated and damage inducible, Steve was on his way.

It is hard to trace Steve's contributions in a linear fashion, because his work has ramified in so many directions. After having moved to Baylor Medical School in 1989 as an Assistant Professor, Steve used the new cloning and expression vectors he had devised to identify Cdk2, a paralog of the one known mammalian cell division kinase, Cdc2. Cdk2 proved to be the key regulator of the G1-to-S transition in mammalian cells. Elledge then teamed up with Wade Harper, a collaboration that continues today, to identify and characterize p21 as an inhibitor of Cdk2, simultaneously with the Vogelstein lab's demonstration that p21 was regulated by the cancer gene p53. Among the many findings that Elledge made in the mid-1990s was the identification of cyclin F and the finding that degradation of this cyclin is dependent on a specific protein sequence, the F-box. Steve's lab then both identified and characterized the SCF ubiquitin ligase complex that regulates protein degradation and identified a number of new specificity factors that target proteins for timely destruction. One important recent article implicates the F-box ubiquitin ligase Fbw7 in defective cardiovascular development in the mouse, accompanied by elevated levels of cyclin E.

Steve has also made key contributions to the study of the DNA replication and damage checkpoints. Screens of yeast mutants sensitive to the ribonucleotide reductase inhibitor hydroxyurea identified S-phase arrest-defective mutants; these have implicated the Rad53/Chk2 protein kinase and DNA polymerase epsilon protein in preventing mitosis in the presence of stalled replication forks. Another hydroxyurea-sensitive mutant led Elledge into studying aspects of the mitotic spindle. Steve's lab found the human and budding-yeast homologs of the Schizosaccharomyces pombe Chk1 protein kinase and showed that the yeast Chk1 regulated cell cycle progression in a parallel pathway with Chk2/Rad53. His lab has made major contributions to understanding the roles of damage response proteins in mammalian cells. Many articles have focused on the way DNA damage is sensed and how these signals are transduced into altered gene expression and cell cycle arrest. The finding that the essential Chk1 gene in mice exhibits haplo-insufficiency for tumor suppression opens up still more avenues.

And still more useful tools emerged from Steve's lab, including the univector plasmid-fusion system, for rapid construction of recombinant DNA without restriction enzymes and, most recently, new tools for large-scale RNA-interference-based screens in mammals.

The GSA medal honors a remarkable scientist in midcareer. Steve Elledge has been a powerful force in understanding how cells deal with the stresses of replication and DNA damage. He has harnessed the "awesome power of yeast genetics" to trace pathways of cell cycle regulation and then used all of his skills as a molecular biologist to learn the similarities and differences in these processes in mammals. We anticipate many more surprises from Steve Elledge's inventive mind and his passionate love of genetics.

Since 1993, Steve has been an investigator of the Howard Hughes Medical Institute. In 2003 he moved to Harvard Medical School as Professor in the Departments of Genetics and as Geneticist in the Department of Medicine, Brigham and Women's Hospital. Steve has been honored for his many contributions by his election in 2003 to both the U.S. National Academy of Sciences and the American Academy of Arts and Sciences. He has received the DAMD Breast Cancer Innovator Award (2003), the National Academy of Sciences Award in Molecular Biology (2002), the John B. Carter, Jr. Technology Innovation Award (2002), and the Paul Marks Prize for Cancer Research (2001), among others.



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  		Steven J. Elledge