BBS Faculty Member - Stephen Elledge

Stephen Elledge

Department of Genetics

Harvard Medical School
Department of Genetics, NRB, Rm.158D
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: 617-525-4510
Fax: 617-525-4500
Email: selledge@genetics.med.harvard.edu



A major area of our interest is how eukaryotic cells sense and respond to stress in the form of damage to their genetic material. When cells incur DNA damage, they induce the transcription of genes involved in cell cycle arrest and repair of the damage. Failure to do this can result in genomic instability and cancer in humans. We have found that sensors of DNA damage and replication blocks activate a kinase cascade involving the ATR/ATRIP and Chk1 kinases in mammals.

Recently we have developed methods to identify substrates of the DNA damage activated kinases and have found over 700 proteins phosphorylated in response to DNA damage. We have also performed genetic screens in human cells and identified many new DNA damage response genes, which we are working up. This gene list is a rich resource and has already led us to the discovery of new Fanconi anemia genes, FANCI and FAN1, plus SMARCAL1, RANZB3 and the SLX4 recombinase. We are also pursuing genetic and proteomic strategies to identify other important DNA damage response proteins. In addition, we have recently began studying senescence, a potent tumor suppressor pathway that is activated in response to DNA damage. We have identified many new genes involved in senescence and hope to further dissect how this terminal differentiation pathway is driven by p53.

Our other primary interest is in generating genetic technologies. We have generated ORF libraries and shRNA libraries in retroviral vectors to perform gain of function and loss of function genetic screens and use these in unraveling human diseases such as cancer. Our first screen involved searching for genes whose loss confers tumor-like properties on mammary epithelial cells. We identified a number of genes previously implicated in cancer and multiple new tumor suppressors using this strategy including PTPN12 a new tyrosine phosphatase that opposes Her2 signaling in breast cancer. We also identified genes required for survival of cancer cells and potential new drug target candidates and performed a Myc synthetic lethal screen that identified a role for SUMO and mitotic functions in the survival of cells overexpressing Myc. Finally, we have developed algorithms to identify cancer drivers in sequences from 8200 tumors. These tumor suppressors and oncogenes make up over 90-95% of all potent cancer drivers. We found that by analyzing their distributions along chromosomes, we can predict the frequency at which chromosomes are lost or gained in cancer. Thus, aneuploidy is not simply a byproduct of cancer but a driver of tumorigenesis in its own right. We are now performing systems analysis of these cancer genes to understand how these genes drive cancer.



Last Update: 6/18/2014



Publications

For a complete listing of publications click here.

 


 

Cotta-Ramusino, C., McDonald, E.R. 3rd., Hurov, K., Sowa, M.E., Harper, J.W., Elledge, S.J. (2011) A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling. Science. 332:1313-7.

Davoli, T., Xu, A.W., Mengwasser, K.E., Sack, L.M., Yoon, J.C., Park, P.J., and Elledge, S.J. (2013) Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns to Shape the Cancer Genome.
Cell 155: 948-962.

Solimini, N.L., Xu, Q., Mermel ,C.H., Liang, A.C., Schlabach, M.R., Luo, J., Burrows, A.E., Anselmo, A.N., Bredemeyer ,A.L., Li M.Z., Beroukhim, R., Meyerson, M., Elledge, S.J. (2012) Recurrent Hemizygous Deletions in Cancers May Optimize Proliferative Potential.
Science 337:104-109.

Ciccia A, Nimonkar AV, Hu Y, Hajdu I, Achar YJ, Izhar L, Petit SA, Adamson B, Yoon JC, Kowalczykowski SC, Livingston DM, Haracska L, Elledge SJ. (2012) Polyubiquitinated PCN Recruits the ZRANB3 Translocase to maintain Genomic Integrity after Replication Stress.
Mol. Cell 47:396-409. PMID:22704558



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