Genetics, Molecular Biology
Brigham and Women's Hospital
Dr. Elledge is also Gregor Mendel Professor of Genetics in the Department of Genetics at Harvard Medical School and the Division of Genetics at Brigham and Women's Hospital.
The Genetics of Human Regulatory Systems
Stephen Elledge uses genetics and genetic technologies to solve problems relevant to human disease. His team has uncovered many of the proteins that safeguard the genome by sensing and responding to the presence of DNA damage, orchestrating its repair, and ensuring the integrity of chromosomes before cells divide. Mutations in many of the genes involved in this DNA damage response (DDR) can cause genomic instability and cancer.
Elledge’s team is also developing new immunological tools to probe autoimmunity and viral function. One technology they created, called VirScan, detects antibodies against all human viruses in blood. Using a single drop of blood, the method enables researchers to test for current and past viral infections.
Elledge’s team recently identified multiple genes that control cell proliferation. The scientists are using this information to reconstruct the higher-order regulatory networks that drive the cell cycle and cancer proliferation. The group has also uncovered many new tumor suppressors and oncogenes by examining the mutational profiles of tumors. They discovered that the distribution of these genes on chromosomes is predictive of the pattern of aneuploidy seen in cancers, providing a new hypothesis of how aneuploidy drives tumorigenesis.
Another area of study in the Elledge lab is cellular senescence – a terminal, stress-activated program controlled by the p53 and p16INK4a tumor suppressor proteins. A striking feature of this cellular process is the senescence-associated secretory phenotype (SASP), a proinflammatory response linked to tumor promotion and aging. Elledge’s lab team discovered that the transcription factor GATA4 is stabilized in cells undergoing senescence and is required for the SASP. GATA4 accumulates in multiple tissues during aging, including the brain, and could contribute to age-associated inflammation. Understanding how GATA4 is activated and understanding the significance of its role in human health are among Elledge’s future areas of interest.
Geneticist Stephen Elledge has uncovered important drivers of the cell cycle – the predictable yet complex series of steps that culminates in cell division – and helped reveal how eukaryotic cells sense and respond to DNA damage. He has also pushed science forward by developing new technologies involving gene expression, protein stability detection, protein-protein interactions, RNA interference, and antibody detection, and by sharing these tools with the scientific community.
Elledge, who was the first in his family to go to college, majored in chemistry at the University of Illinois. When he learned about recombinant DNA in a biochemistry course, he knew exciting times were ahead for the field of biology. “I wanted to be a part of that revolution,” he remembers.
While pursuing a PhD at the Massachusetts Institute of Technology, Elledge made a hobby out of developing new methods for generating recombinant DNA. He shared the tools and techniques he created, enabling other scientists to efficiently identify protein-protein interactions relevant to their own research.
During a postdoctoral fellowship at Stanford University, Elledge cloned a family of genes known as ribonucleotide reductases, and showed that they are activated by DNA damage and regulated by the cell cycle. Soon after this discovery, Elledge attended a lecture by Paul Nurse, who later won the Nobel Prize in Physiology or Medicine for his cell cycle research. Nurse’s studies indicated that cell cycle regulation had been functionally conserved through evolution and that human cell cycle genes could be identified by looking for complementary genes in yeast.
That work struck a chord with Elledge, and he set about building a human cDNA library that could be expressed in yeast. Using this library, he identified a gene known as Cdk2, which controls a key cell cycle transition. Errors in this step often lead to cancer. Elledge and his colleagues also identified two inhibitors of Cdk2, dubbed p21 and p57. Mutations in these genes are associated with an increased risk of cancer.
While looking for additional cell cycle genes, Elledge and his colleagues identified the F-box, a structural motif that is present in some proteins. F-box-containing proteins recognize specific protein sequences, often generated by phosphorylation, and mark them for destruction by the cell’s built-in shredder – the proteasome. Increased levels of certain proteins can disrupt the cell cycle, so destroying them is one way to ensure that cells continue to divide normally or stop dividing altogether.
Elledge has also made important discoveries about how cells detect and repair DNA damage. He identified the ATR/ATRIP DNA damage sensor that activates a signal transduction cascade, including the Chk1 and Chk2 enzymes, which help prevent cells with damaged DNA from dividing and activate DNA repair. Mutations in this DNA damage response pathway increase the risk of cancer. In other studies, he demonstrated that a protein known as ATM triggers the protein BRCA1 to repair DNA damage. Mutations in ATM and BRCA1 together may account for nearly 10 percent of all breast cancers.
For Elledge, research is not merely an academic exercise. “By contributing to basic research, I hope my work can accelerate discoveries to improve the lives and health of people,” he says.