Dickson Prize in Medicine Lecture
Stephen J. Elledge, PhD
Stephen J. Elledge, PhD, is one of the world’s leading and most prolific scientists in the field of cell cycle regulation and the cellular response to genotoxic stress. As a postdoctoral fellow at Stanford working on eukaryotic homologous recombination, he serendipitously found a family of genes known as ribonucleotide reductases. He subsequently showed that these genes are activated by DNA damage and could serve as tools to help scientists dissect the signaling pathways through which cells sense and respond to DNA damage and replication stress. Elledge’s work in this area led to his first academic appointment as assistant professor of biochemistry at Baylor College of Medicine. There he made a second major breakthrough with the discovery of the cyclin-dependent kinase 2 gene (Cdk2), which controls the G1-to-S cell cycle transition, an entry checkpoint for the cell proliferation cycle and a critical regulatory step in tumorigenesis. From there, using a novel “two-hybrid” cloning method he developed, Elledge and Wade Harper, PhD, proceeded to isolate several members of the Cdk2-inhibitory family. Their discoveries included the p21 and p57 genes, mutations in the latter of which are responsible for Beckwith-Wiedemann syndrome, a disease characterized by somatic overgrowth and increased cancer risk.
Elledge is also recognized for his work in understanding proteome remodeling through ubiquitin-mediated proteolysis. He identified F-box proteins that regulate protein degradation in the cell by binding to specific target protein sequences and then marking them with ubiquitin for destruction by the cell’s proteasome machinery. This breakthrough resulted in the elucidation of the cullin ubiquitin ligase family, which controls regulated protein stability in eukaryotes.
In recent years, Elledge’s research has focused on the cellular mechanisms underlying DNA damage detection and cancer using genetic technologies. In collaboration with Cold Spring Harbor Laboratory researcher Gregory Hannon, PhD, Elledge has generated complete human and mouse short hairpin RNA (shRNA) libraries for genome-wide loss-of-function studies. Their efforts have led to the identification of a number of tumor suppressor proteins as well as genes upon which cancer cells uniquely depend for survival. This work led to the development of the “non-oncogene addiction” concept.
Elledge received his PhD in biochemistry from the Massachusetts Institute of Technology and completed a postdoctoral fellowship at Stanford University. After 14 years on the faculty of Baylor College of Medicine, Elledge was recruited to Harvard Medical School in 2003, where he currently serves as Gregor Mendel Professor of Genetics and Medicine. He is a Howard Hughes Medical Institute investigator and has been elected to the National Academy of Sciences, the American Academy of Arts and Sciences, and the Institute of Medicine. He is the recipient of numerous honors and awards, including the Paul Marks Prize for Cancer Research, the Genetics Society of America Medal, and the G.H.A. Clowes Memorial Award from the American Association for Cancer Research.